V1a Receptor Agonists

ABSTRACT

Compounds of formula (I), salts thereof, and compositions and uses thereof are described. The compounds are useful as V1a vasopressin agonists, for the treatment of e.g., complications of cirrhosis, including bacterial peritonitis, HRS2 and refractory ascites.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/645,558, filed May 10, 2012, the entire disclosure of which is herebyincorporated by reference.

TECHNICAL FIELD

This disclosure relates to peptide compounds, and more particularly tocompounds which have partial V1a receptor agonist activity, compositionscontaining such compounds and uses of such compounds.

BACKGROUND

The vasopressin-vasopressin receptor system is involved in two keyhomeostatic functions. A principal function of vasopressin is toregulate osmolality of the blood through the V2 receptor (V2R) found inthe kidney. A second function of vasopressin is as a pressor agent whichis mediated by the V1a receptor (V1aR) found on blood vessels.

Experimentation has been performed with a number of vasopressin receptoragonists and antagonists for use in the treatment of a variety ofdiseases. Lenz, et al., Gut, 1985, 26(12), 1385-1386; Lenz, et al., Gut,1989, 30(1), 90-96; Russell, et al., N. Engl. J. Med., 2008, 358(9),877-887; Fimiani, et al., Eur. J. Intern. Med., 2011, 22(6), 587-590;Cardenas, et al., J. Hepatol., 2012, 56(3), 571-578; Sanyal, et al.,Gastroenterol., 2008, 134(5), 1360-1368.

Of particular clinical interest is the use of vasopressin agonists fortheir pressor activity in patients with hypovolemia or hypotension inorder to elevate arterial pressure. A significant drawback of existingfull vasopressin agonists for this use is the potential to induce severevasoconstriction and tissue hypoperfusion when used at pharmacologicaldoses. Gulberg, et al., Hepatol., 1999, 30(4), 870-875; Yefet, et al.,Isr. Med. Assoc. J., 2011, 13(3), 180-181; Sanyal, et al.,Gastroenterol., 2008, 134(5), 1360-1368. The narrow therapeutic index ofthese compounds has restricted their use to patients where the risk oftissue hypoperfusion is acceptable due to the severity of the underlyingcondition being treated.

The V2 receptor (V2R) is primarily found in the kidneys, in particularon the principal cells of the collecting ducts, where it is responsiblefor concentrating urine by reabsorbing water from the glomerularultrafiltrate. This water retention can lead to hyponatremia if fluidintake is not restricted proportionately. The V2R is also found atextra-renal locations such as on endothelial cells where it appears tobe responsible for a variety of effects, including release of vonWillebrand factor and nitric oxide. The V1a receptor (V1aR) is primarilyfound on smooth muscle cells throughout the vasculature where it acts asa key regulator of vascular tone. The vasopressin analog, terlipressin,has been approved in some countries for the treatment of severalcirrhotic complications (bleeding esophageal varices and type 1hepatorenal syndrome) and has been used to demonstrate the utility ofusing vasoconstriction to treat other cirrhotic complications(spontaneous bacterial peritonitis, type-2 hepatorenal syndrome and postparacentesis circulatory dysfunction).

Cirrhosis of the liver is a common end stage of excessive alcoholconsumption or of hepatitis. In about a third of cirrhosis patients,fluid builds up in the peritoneal cavity, and this is controlled byparacentesis. Complications of paracentesis include hypovolaemia and anundesirable fall in arterial blood pressure. These have traditionallybeen checked by infusion of human albumin, and more recently,terlipressin.

The development of portal hypertension as a consequence of cirrhosis isthe key factor in the cardiovascular complications associated withend-stage liver disease. The liver has a normal hepatic venous pressuregradient (HVPG) of 1-5 mm Hg. An increase in HVPG is caused by activeand passive increases in intrahepatic vascular resistance associatedwith the development of cirrhosis. This triggers a reflex splanchnicarteriolar vasodilation leading to increase in portal blood flow andfurther contributes to the increase in HVPG diagnosed as portalhypertension once it exceeds 12 mm Hg. This shift of the total bloodvolume towards the splanchnic circulation leads to a decrease in theeffective blood volume (i.e., blood volume in the central portion of thecardiovascular system), which triggers reflex mechanisms aiming atincreasing blood volume, essentially sodium and water retentionmechanisms and vasoconstrictor mechanisms, further increasing theintensity of blood volume shift towards the splanchnic circulation whichincreases portal blood flow. Eventually, worsening vasoconstriction atthe kidney starts reducing renal blood flow leading to either chronic(type II hepatorenal syndrome, HRS2) or acute renal failure (type Ihepatorenal syndrome; HRS1) depending on the speed of deterioration.Both types of renal failure are very difficult to manage clinically(i.e., reversing excessive renal vasoconstriction) without worseningsplanchnic vasodilation and portal hypertension.

Current medical management of the most severe cardiovascularcomplications of cirrhosis primarily relies on either vasoconstrictortherapy or albumin administration. Vasoconstrictor therapy targeted tospecifically reduce splanchnic vasodilation without furtherdeteriorating renal blood flow is the therapeutic intervention ofchoice. However, there is no current “gold standard” of care, asavailable vasoconstrictive agents tend to have significant liabilities,such as an ineffective degree of splanchnic vasoconstriction and/orexcessive degree of extra-splanchnic vasoconstriction, too short aduration of action, or too narrow a therapeutic window. In Europeancountries, the emerging standard of care for the treatment of HRS1 isadministration of terlipressin. Other earlier, less severe complicationsof cirrhosis are often managed with albumin as a volume expander in theabsence of a safe vasoconstrictor.

Terlipressin has been shown to be effective in treating HRS1 in alarge-scale, randomized, placebo-controlled, blinded clinical trial(Orphan Therapeutics), providing proof of concept that vasoconstrictioncan be effective in treating renal failure in the context of cirrhosis(HRS1). Although the trial did not achieve its primary endpoint(survival with a reversal of HRS), terlipressin will likely become thetherapeutic of choice for HRS1 in the regions of the world where it isapproved. While terlipressin is considered better than fluid/albumintherapy alone, it is only able to reverse renal failure in 30-40% ofpatients, leaving room for improvement. Terlipressin has demonstratedclinical efficacy in bleeding esophageal varices (BEV) and HRS1, but ithas drawbacks such as a relatively short duration of action when used atlower, and hence safer, doses, and too much extra-splanchnicvasoconstriction at higher doses. It is not practical to useterlipressin outside of a monitored, inpatient setting due to its needfor frequent dosing (every 4-6 h or via IV infusion) and the potentialfor severe adverse events. While these severe adverse events areuncommon, they are potentially life threatening and must be managedaccordingly.

SUMMARY

The present disclosure provides a compound according to formula (I):

or a salt thereof, wherein:

R¹ is selected from (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylNH,Ar¹-L¹- and unsubstituted or substituted cycloalkyl;

Ar¹-L¹- is selected from Ar¹—, Ar¹—CH₂—, Ar¹—CH₂CH₂—, Ar¹—O—, Ar¹—CH₂O—,Ar¹—NH— and Ar¹—CH₂NH—;

Ar¹ is unsubstituted aryl or substituted aryl;

R² is selected from hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy andhalogen;

R³ is selected from (C₁-C₆)alkyl, unsubstituted or substitutedcycloalkyl and Cy³-CH₂—;

Cy³- is unsubstituted or substituted aryl or unsubstituted orsubstituted cycloalkyl;

R⁴ is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, ((C₁-C₆)alkylene)-OR^(4a), —((C₁-C₆)alkylene)-NR^(4a)₂, —((C₁-C₆)alkylene)-S(C₁-C₆)alkyl, ((C₁-C₆)alkylene)C(═O)OR^(4a) ₂,—((C₁-C₆)alkylene)-C(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)-C(═NR^(4a))NR^(4a)₂, —((C₁-C₆)alkylene)-OC(═O)R^(4a), —((C₁-C₆)alkylene)-OC(═O)OR^(4a),—((C₁-C₆)alkylene)-OC(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)NR^(4a)C(═O)R^(4a),—((C₁-C₆)alkylene)NR^(4a)C(═O)OR^(4a),—((C₁-C₆)alkylene)NR^(4a)C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═NR^(4a))NR^(4a) ₂, Ar⁴ and—((C₁-C₆)alkylene)-Ar⁴;

each R^(4a) is independently selected from hydrogen and (C₁-C₆)alkyl;

Ar⁴ is selected from unsubstituted or substituted aryl and unsubstitutedor substituted heteroaryl;

R⁵ is selected from —((C₁-C₆)alkylene)-NR^(5a) ₂ and—((C₁-C₆)alkylene)-NR^(5a)C(═NR^(5a))NR^(5a) ₂;

each R^(5a) is independently selected from hydrogen and (C₁-C₆)alkyl;

Q is selected from the groups Q¹, Q², Q³ and Q⁴:

a and b denote the bonds attaching Q to the remainder of the molecule;

R⁶ is selected from hydrogen, (C₁-C₆)alkyl and —C(═NR^(6a))NR⁶⁹ ₂;

each R^(6a) is independently hydrogen or (C₁-C₆)alkyl;

R⁷ is selected from (C₁-C₆)alkyl, unsubstituted aryl, substituted aryl,unsubstituted cycloalkyl and substituted cycloalkyl;

R⁸ is selected from NH₂ and hydroxyl;

R⁹ is selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, ((C₁-C₆)alkylene)-OR^(9a),—((C₁-C₆)alkylene)-NR^(9a) ₂; —((C₁-C₆)alkylene)-SR^(9a),((C₁-C₆)alkylene)C(═O)OR^(9a) ₂, —((C₁-C₆)alkylene)-C(═O)NR^(9a) ₂,—((C₁-C₆)alkylene)-C(═NR^(9a))NR^(9a) ₂,—((C₁-C₆)alkylene)-OC(═O)R^(9a), —((C₁-C₆)alkylene)-OC(═O)OR^(9a),—((C₁-C₆)alkylene)-OC(═O)NR⁹a₂, —((C₁-C₆)alkylene)-NR^(9a)C(═O)R^(9b),—((C₁-C₆)alkylene)-NR^(9a)C(═O)OR^(9a),—((C₁-C₆)alkylene)NR^(9a)C(═O)NR⁹a₂,—((C₁-C₆)alkylene)-NR^(9a)C(═NR^(9a))NR^(9a) ₂, Ar⁹ and—((C₁-C₆)alkylene)-Ar⁹;

each R^(9a) is independently selected from hydrogen and (C₁-C₆)alkyl;

each R^(9b) is independently selected from hydrogen and (C₁-C₁₀)alkyl;

Ar⁹ is selected from unsubstituted aryl, substituted aryl, unsubstitutedheteroaryl substituted heteroaryl;

R¹⁰ is selected from —((C₁-C₆)alkylene)-OR^(10a),—((C₁-C₆)alkylene)-C(═O)NR^(10a) ₂ and Ar¹⁰—CH₂—;

Ar¹⁰ is unsubstituted heteroaryl or substituted heteroaryl;

each R^(10a) is selected from hydrogen and (C₁-C₆)alkyl;

Ar is selected from aryl or substituted aryl;

each X is NH and each Y is C═O; or each X is C═O and each Y is NH;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

o is 1 or 2;

p is 1, 2 or 3; and

r is 0, 1, 2, 3, 4, 5 or 6; provided that R⁹ is hydrogen if r is greaterthan one.

Various embodiments of the disclosed compounds, including exemplarycompounds are described.

Also described is a pharmaceutical composition that includes a compoundof formula (I), or any of the embodiments thereof, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Methods of treatment using the compounds of formula (I) are alsodescribed. The methods include administering an effective amount of thecompound of formula (I) or any of the embodiments thereof, or apharmaceutically acceptable salt thereof, to an individual in need ofthe treatment.

The compounds are also useful for treating complications arising fromcirrhosis, e.g., when increasing blood pressure is therapeuticallydesirable. Complications of cirrhosis that can be treated with theclaimed compounds include bacterial peritonitis, type II heptoarenalsyndrome or refractory ascites. The compounds are also useful, e.g., forincreasing blood pressure. The compounds are also useful for treatinghypovolemic shock; vasodilatory shock; bleeding esophageal varices;hepatorenal syndrome; type I hepatorenal syndrome; type II hepatorenalsyndrome; anesthesia-induced hypotension; paracentesis-inducedcirculatory dysfunction; intra-operative blood loss; acute hemorrhage;blood loss associated with burn debridement; blood loss associated withepistaxis; spontaneous bacterial peritonitis; refractory ascites;hypertensive gastropathy bleeding; sepsis; severe sepsis; septic shock;hypotension, including orthostatic hypotension and intradialytichypotension; cardiac arrest; trauma-related blood loss; vasodilatoryshock induced by cardio-pulmonary bypass; milrinone-induced vasodilatoryshock in congestive heart failure; anaphylactic shock; cardiovascularinstability induced by brain death; acute respiratory distress syndrome;acute lung injury; shock induced by metformin intoxication; shockinduced by mitochondrial disease; shock induced by cyanide poisoning;shock induced by vascular leak syndrome induced by interleukin-2,another cytokine, denileukin diftitox or another immunotoxin, or byovarian hyperstimulation syndrome; hypotension induced by end-stagerenal disease; inflammatory bowel disease; reperfusion injury; infantrespiratory distress syndrome; severe acute respiratory syndrome;ascites; vasodepressor syncope; vasovagal syncope; toxic shock syndrome;and idiopathic systemic capillary leak syndrome.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure relates. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods and examples are illustrative only and not intendedto be limiting.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects andadvantages will be apparent from the description and drawings, and fromthe claims.

DETAILED DESCRIPTION

While not being limited by any theory, it is believed that a V1avasopressin agonist with a ceiling on its vasoconstrictive potential canbe used for treatment using a bolus dosing paradigm that can providelong duration of action with a consistent level of vasoconstriction,thereby dramatically improving safety, convenience and clinical efficacyin the reversal of renal failure associated with cirrhoticcomplications. It is believed that such compounds can provide improvedsafety allowing the use of such a vasoconstrictor in low intensityclinical settings or even as an outpatient product, thereby enabling thetreatment of conditions such as spontaneous bacterial peritonitis, HRS2and refractory ascites.

The disclosure describes selective, partial V1a agonists that cansubstantially deliver the clinical benefits of terlipressin, whileproviding improved safety and convenience through longer duration ofaction than terlipressin. Undesired fluctuations in vasoconstrictiveeffect are also thereby reduced. Such compounds could become thetherapeutic agents of choice in the treatment of cardiovascularcomplications where reduction of portal hypertension is clinicallyefficacious. These advantages can enable the practical treatment ofcirrhotic complications generally, where a full agonist compound wouldnot be suitable.

Existing full agonist compounds such as terlipressin have a narrowtherapeutic index. As the concentration of a full agonist drugincreases, it is possible to exceed the therapeutic level ofvasoconstriction and cause excessive vasoconstriction. This can resultin severe tissue hypoxia and ischemia. Reduced maximal efficacy or“partial efficacy” compounds will be able to be used at much higherconcentrations than would be possible with existing full agonistcompounds while not causing undesired additional vasoconstriction. Themaximal vasoconstrictive effect that is attainable with such compoundsis reduced due to submaximal agonist activation of the V1a receptor.

In the present disclosure, it is appreciated that certain featuresdescribed herein, which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a singleembodiment. Conversely, various features described herein which are, forbrevity, described in the context of a single embodiment, can also beprovided separately or in any suitable subcombination.

I. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs.

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means “approximately” (e.g., plus orminus approximately 10% of the indicated value).

As used herein, a “partial V1a agonist” is a compound which providesagonism (as determined by the FLIPR assay described herein) at the humanV1a receptor of between about 15% and about 70% of that provided byarginine vasopressin (AVP), which is considered a full V1a agonist.

As used herein, “alkyl” refers to a saturated hydrocarbon chain that maybe a straight chain or a branched chain. An alkyl group formallycorresponds to an alkane with one C—H bond replaced by the point ofattachment of the alkyl group to the remainder of the compound. The term“(C_(X)-C_(y))alkyl” (wherein x and y are integers) by itself or as partof another substituent means, unless otherwise stated, an alkyl groupcontaining from x to y carbon atoms. For example, a (C₁-C₆)alkyl groupmay have from one to six (inclusive) carbon atoms in it. Examples of(C₁-C₆)alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl,tert-butyl, isopentyl, neopentyl and isohexyl. The (C_(X)-C_(y))alkylgroups include (C₁-C₁₀)alkyl, (C₁-C₆)alkyl, (C₁-C₄)alkyl and(C₁-C₃)alkyl.

The term “(C_(X)-C_(y))alkylene” (wherein x and y are integers) refersto an alkylene group containing from x to y carbon atoms. An alkylenegroup formally corresponds to an alkane with two C—H bonds replaced bypoints of attachment of the alkylene group to the remainder of thecompound. Examples are divalent straight hydrocarbon groups consistingof methylene groups, such as, —CH₂—, —CH₂CH₂— and —CH₂CH₂CH₂—. The(C_(X)-C_(y))alkylene groups include (C₁-C₆)alkylene and(C₁-C₃)alkylene.

As used herein, “alkoxy” refers to the group R—O— where R is an alkylgroup, as defined above. The term “(C_(x)-C_(y))alkoxy” (wherein x and yare integers) by itself or as part of another substituent means, unlessotherwise stated, an alkyl group containing from x to y carbon atoms.(C₁-C₆)alkoxy groups include, but are not limited to, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and t-butoxy. The (C_(X)-C_(y))alkoxygroups include (C₁-C₆)alkoxy and (C₁-C₃)alkoxy.

As used herein, “alkenyl” refers to an unsaturated hydrocarbon chainthat includes a C═C double bond. An alkenyl group formally correspondsto an alkene with one C—H bond replaced by the point of attachment ofthe alkenyl group to the remainder of the compound. The term“(C_(X)-C_(y))alkenyl” (wherein x and y are integers) denotes a radicalcontaining x to y carbons, wherein at least one carbon-carbon doublebond is present (therefore x must be at least 2). Some embodiments are 2to 4 carbons, some embodiments are 2 to 3 carbons and some embodimentshave 2 carbons. Alkenyl groups may include both E and Z stereoisomers.An alkenyl group can include more than one double bond. Examples ofalkenyl groups include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl, and the like.

As used herein, “alkynyl” refers to an unsaturated hydrocarbon chainthat includes a CC triple bond. An alkynyl group formally corresponds toan alkyne with one C—H bond replaced by the point of attachment of thealkyl group to the remainder of the compound. The term“(C_(X)-C_(y))alkynyl” (wherein x and y are integers) denotes a radicalcontaining x to y carbons, wherein at least one carbon-carbon triplebond is present (therefore x must be at least 2). Some embodiments are 2to 4 carbons, some embodiments are 2 to 3 carbons and some embodimentshave 2 carbons. Examples of an alkynyl include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl and the like. The term “alkynyl” includes di- and tri-ynes.

As used herein, “halo” or “halogen” refers to —F, —Cl, —Br and —I.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “(C_(x)-C_(y))haloalkyl” (wherein x and y are integers) byitself or as part of another substituent means, unless otherwise stated,an alkyl group containing from x to y carbon atoms. The alkyl may besubstituted with one halogen up to fully substituted, e.g., asrepresented by the formula C_(n)F_(2n+1); when more than one halogen ispresent they may be the same or different and selected from F, Cl, Br orI. Some embodiments are 1 to 3 carbons. Haloalkyl groups may bestraight-chained or branched. Examples include fluoromethyl,difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like. The term“perfluoroalkyl” denotes the group of the formula —C_(n)F_(2n+1); stateddifferently, a perfluoroalkyl is an alkyl as defined herein wherein thealkyl is fully substituted with fluorine atoms and is thereforeconsidered a subset of haloalkyl. Examples of perfluoroalkyls includeCF₃, CF₂CF₃, CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃, CF₂CF(CF₃)₂,CF(CF₃)CF₂CF₃ and the like.

As used herein, “cycloalkyl” refers to a non-aromatic, saturated,monocyclic, bicyclic or polycyclic hydrocarbon ring system. The term“(C_(X)-C_(y)) cycloalkyl” (wherein x and y are integers) denotes acycloalkyl group containing from x to y carbon atoms in the ring.Cycloalkyl groups include (C₃-C₁₂)cycloalkyl, (C₅-C₇)cycloalkyl and(C₆)cycloalkyl. Representative examples of a (C₃-C₁₂)cycloalkyl include,but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl,cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl,decahydro-1H-benzo[7]annulen-2-yl and dodecahydros-indacen-4-yl.Representative examples of a (C₃-C₁₀)cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl andoctahydro-1H-inden-2-yl. Representative examples of a (C₃-C₈)cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and octahydropentalen-2-yl.

A cycloalkyl can be unsubstituted or substituted. A substitutedcycloalkyl can be substituted with one or more groups, e.g., 1, 2 or 3groups, including: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —C(═O)R, —C(═O)OR, —C(═O)NR₂,—C(═NR)NR₂, —NR₂, —NRC(═O)R, —NRC(═O)O(C₁-C₆)alkyl, —NRC(═O)NR₂,—NRC(═NR)NR₂, —NRSO₂R, —OR, —O(C₁-C₆)haloalkyl, —OC(═O)R,—OC(═O)O(C₁-C₆)alkyl, —OC(═O)NR₂, —SR, —S(O)R, —SO₂R, —OSO₂(C₁-C₆)alkyl,—SO₂NR₂, —(C₁-C₆)alkylene-CN, —(C₁-C₆)alkylene-C(═O)OR,—(C₁-C₆)alkylene-C(═O)NR₂, —(C₁-C₆)alkylene-OR,—(C₁-C₆)alkylene-OC(═O)R, —(C₁-C₆)alkylene-NR₂,—(C₁-C₆)alkylene-NRC(═O)R, —NR(C₁-C₆)alkylene-C(═O)OR,—NR(C₁-C₆)alkylene-C(═O)NR₂, —NR(C₂-C₆)alkylene-OR,—NR(C₂-C₆)alkylene-OC(═O)R, —NR(C₂-C₆)alkylene-NR₂,—NR(C₂-C₆)alkylene-NRC(═O)R, —O(C₁-C₆)alkylene-C(═O)OR,—O(C₁-C₆)alkylene-C(═O)NR₂, —O(C₂-C₆)alkylene-OR,—O(C₂-C₆)alkylene-OC(═O)R, —O(C₂-C₆)alkylene-NR₂ and—O(C₂-C₆)alkylene-NRC(═O)R. Each R can be, independently, hydrogen or(C₁-C₆)alkyl. Additionally, each of any two hydrogen atoms on the samecarbon atom of the carbocyclic ring can be replaced by an oxygen atom toform an oxo (═O) substituent.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized it (pi) electrons where n is an integer).

As used herein, “aryl,” employed alone or in combination with otherterms, refers to an aromatic hydrocarbon group. The aryl group may becomposed of, e.g., monocyclic or bicyclic rings and may contain, e.g.,from 6 to 12 carbons in the ring, such as phenyl, biphenyl and naphthyl.The term “(C_(X)-C_(y))aryl” (wherein x and y are integers) denotes anaryl group containing from x to y ring carbon atoms. Examples of a(C₆-C₁₄)aryl group include, but are not limited to, phenyl, α-naphthyl,β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl,biphenylenyl and acenanaphthyl. Examples of a C₆-C₁₀ aryl group include,but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl andtetrahydronaphthyl.

An aryl group can be unsubstituted or substituted. A substituted arylgroup can be substituted with one or more groups, e.g., 1, 2 or 3groups, including: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —C(═O)R, —C(═O)OR, —C(═O)NR₂,—C(═NR)NR₂, —NR₂, —NRC(═O)R, —NRC(═O)O(C₁-C₆)alkyl, —NRC(═O)NR₂,—NRC(═NR)NR₂, —NRSO₂R, —OR, —O(C₁-C₆)haloalkyl, —OC(═O)R,—OC(═O)O(C₁-C₆)alkyl, —OC(═O)NR₂, —SR, —S(O)R, —SO₂R, —OSO₂(C₁-C₆)alkyl,—SO₂NR₂, —(C₁-C₆)alkylene-CN, —(C₁-C₆)alkylene-C(═O)OR,—(C₁-C₆)alkylene-C(═O)NR₂, —(C₁-C₆)alkylene-OR,—(C₁-C₆)alkylene-OC(═O)R, —(C₁-C₆)alkylene-NR₂,—(C₁-C₆)alkylene-NRC(═O)R, —NR(C₁-C₆)alkylene-C(═O)OR,—NR(C₁-C₆)alkylene-C(═O)NR₂, —NR(C₂-C₆)alkylene-OR,—NR(C₂-C₆)alkylene-OC(═O)R, —NR(C₂-C₆)alkylene-NR₂,—NR(C₂-C₆)alkylene-NRC(═O)R, —O(C₁-C₆)alkylene-C(═O)OR,—O(C₁-C₆)alkylene-C(═O)NR₂, —O(C₂-C₆)alkylene-OR,—O(C₂-C₆)alkylene-OC(═O)R, —O(C₂-C₆)alkyleneNR₂ and—O(C₂-C₆)alkyleneNRC(═O)R. Each R can be, independently, hydrogen or(C₁-C₆)alkyl.

The term “heteroaryl” or “heteroaromatic” as used herein refers to anaromatic ring system having at least one heteroatom in at least onering, and from 2 to 9 carbon atoms in the ring system. The heteroarylgroup has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4nitrogen atoms in the ring, and may be bonded to the remainder of themolecule through a carbon or heteroatom. Exemplary heteroaryls includefuryl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl orisoquinolinyl, and the like. The heteroatoms of the heteroaryl ringsystem can include heteroatoms selected from one or more of nitrogen,oxygen and sulfur.

Examples of non-aromatic heterocycles include monocyclic groups such as:aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include: pyridyl, pyrazinyl, pyrimidinyl,particularly 2- and 4-pyrimidinyl, pyridazinyl, thienyl, furyl,pyrrolyl, particularly 2-pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, particularly 3- and 5-pyrazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include: indolyl, particularly 3-,4-, 5-, 6- and 7-indolyl, indolinyl, quinolyl, tetrahydroquinolyl,isoquinolyl, particularly 1- and 5-isoquinolyl,1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl, particularly 1-and 5-quinoxalinyl, quinazolinyl, phthalazinyl, 1,5-naphthyridinyl,1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin,benzofuryl, particularly 3-, 4-, 5-, 6- and 7-benzofuryl,2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl, particularly3-, 4-, 5-, 6- and 7-benzothienyl, benzoxazolyl, benzthiazolyl,particularly 2-benzothiazolyl and 5-benzothiazolyl, purinyl,benzimidazolyl, particularly 2-benzimidazolyl and benztriazolyl.

A heteroaryl group can be unsubstituted or substituted. A substitutedheteroaryl group can be substituted with one or more groups, e.g., 1, 2or 3 groups, including: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,halogen, (C₁-C₆)haloalkyl, CN, —NO₂, —C(═O)R, —C(═O)OR, C(═O)NR₂,—C(═NR)NR₂, —NR₂, —NRC(═O)R, —NRC(═O)O(C₁-C₆)alkyl, —NRC(═O)NR₂,—NRC(═NR)NR₂, NRSO₂R, —OR, —O(C₁-C₆)haloalkyl, —OC(═O)R,—OC(═O)O(C₁-C₆)alkyl, OC(═O)NR₂, —SR, —S(O)R, —SO₂R, —OSO₂(C₁-C₆)alkyl,SO₂NR₂, (C₁-C₆)alkylene-CN, —(C₁-C₆)alkylene-C(═O)OR,—(C₁-C₆)alkylene-C(═O)NR₂, —(C₁-C₆)alkylene-OR,—(C₁-C₆)alkylene-OC(═O)R, —(C₁-C₆)alkyleneNR₂, —(C₁-C₆)alkyleneNRC(═O)R,—NR(C₁-C₆)alkylene-C(═O)OR, —NR(C₁-C₆)alkylene-C(═O)NR₂,—NR(C₂-C₆)alkylene-OR, —NR(C₂-C₆)alkylene-OC(═O)R,—NR(C₂-C₆)alkyleneNR₂, —NR(C₂-C₆)alkyleneNRC(═O)R,—O(C₁-C₆)alkylene-C(═O)OR, —O(C₁-C₆)alkylene-C(═O)NR₂,—O(C₂-C₆)alkylene-OR, —O(C₂-C₆)alkylene-OC(═O)R, —O(C₂-C₆)alkyleneNR₂and —O(C₂-C₆)alkyleneNRC(═O)R. Each R can be, independently, hydrogen or(C₁-C₆)alkyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative and not limiting.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, namely mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.

In the description herein and in the claims, the nomenclature common inthe art of peptide, and more specifically, vasopressin chemistry isused. The amino acids in the substances can be either L- or D-aminoacids. When no configuration is noted, the amino acid is in the L, ornaturally occurring form. The thio members of the p-mercaptopropionicacid (1) and cysteine (6) units are added for clarity in certainstructural formulas. Substances described herein also include peptideswith sequences having reversed peptide bonds. These sequences arepreferably inverted sequences, more preferably comprising D-amino acids.

The term “salt” includes any ionic form of a compound and one or morecounter-ionic species (cations and/or anions). Salts also includezwitterionic compounds (i.e., a molecule containing one more cationicand anionic species, e.g., zwitterionic amino acids). Counter ionspresent in a salt can include any cationic, anionic, or zwitterionicspecies. Exemplary anions include, but are not limited to, chloride,bromide, iodide, nitrate, sulfate, bisulfate, sulfite, bisulfate,phosphate, acid phosphate, perchlorate, chlorate, chlorite,hypochlorite, periodate, iodate, iodite, hypoiodite, carbonate,bicarbonate, isonicotinate, acetate, trichloroacetate, trifluoroacetate,lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,trifluormethansulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, p-trifluoromethylbenzenesulfonate, hydroxide,aluminates and borates. Exemplary cations include, but are not limited,to monovalent alkali metal cations, such as lithium, sodium, potassiumand cesium, and divalent alkaline earth metals, such as beryllium,magnesium, calcium, strontium and barium. Also included are transitionmetal cations, such as gold, silver, copper and zinc, as well asnon-metal cations, such as ammonium salts.

References to the compounds described and disclosed herein areconsidered to include both the free base and all addition salts. Theaddition salts may be either salts with pharmaceutically acceptablecations such as Na⁺, Ca²⁺, K⁺ or Na⁺ at a terminal acid group, such aswhen the C-terminal amino acid is Gly or OH is present, or with apharmaceutically acceptable acid addition salt at a basic center of thepeptide, such as in an Arg unit. The acetate salt forms are useful, andhydrochloride, hydrobromide and salts with other strong acids are alsouseful. In the isolation procedures outlined in the Examples, thepeptide product is often isolated and purified as an acetate salt. Thecompounds may also form inner salts or zwitterions when a free terminalcarboxy group is present. The term “pharmaceutically-acceptable salt”refers to salts which possess toxicity profiles within a range thataffords utility in pharmaceutical applications. Pharmaceuticallyunacceptable salts may nonetheless possess properties such as highcrystallinity, which may render them useful, e.g., in processes ofsynthesis, purification or formulation of compounds described herein. Ingeneral the useful properties of the compounds described herein do notdepend on whether the compound is or is not in a salt form, so unlessclearly indicated otherwise (such as specifying that the compound shouldbe in “free base” or “free acid” form), reference in the specificationto a compound should be understood as including salt forms of thecompound, whether or not this is explicitly stated. Preparation andselection of suitable salt forms is described in Stahl, et al., Handbookof Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH 2002.

When in the solid state, the compounds described herein and saltsthereof may occur in various forms and may, e.g., take the form ofsolvates, including hydrates. In general, the useful properties of thecompounds described herein do not depend on whether the compound or saltthereof is or is in a particular solid state form, such as a polymorphor solvate, so unless clearly indicated otherwise reference in thespecification to compounds and salts should be understood as includingany solid state form of the compound, whether or not this is explicitlystated.

Compounds provided herein can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expression “therapeutically effective amount,” when used to describean amount of compound administered in a method, refers to the amount ofa compound that achieves the desired pharmacological effect or othereffect, e.g., an amount that inhibits the abnormal growth orproliferation, or induces apoptosis of cancer cells, resulting in auseful effect.

The terms “treating” and “treatment” mean causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, preventing orreducing additional symptoms, ameliorating or preventing the underlyingmetabolic causes of symptoms, postponing or preventing the furtherdevelopment of a disorder, and/or reducing the severity of symptoms thatwill or are expected to develop.

The following abbreviations may also be found herein: AcOH (aceticacid); Boc (t-butoxycarbonyl); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIC(N,N′-diisopropylcarbodiimide); DIPEA (N,N-diisopropylethylamine; DME(1,2-dimethoxyethane); DMF (N,N-dimethylformamide); Et (ethyl); Fmoc(9-fluorenylmethylmethoxycarbonyl); h (hour(s)); ivDde(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)3-methylbutyl; HIPF(1,1,1,3,3,3-hexafluoro-2-propanol; HOBt (N-hydroxybenzotriazole); HPLC(high-performance liquid chromatography); LC (liquid chromatography);MeOH (methanol); MS (mass spectrometry); Mtt (4-methyltrityl); NMM(4-methylmorpholine); Pbf(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl); t-Bu (tert-butyl);TEAP (triethylammonium phosphate); TFA (trifluroracetic acid); TFE(2,2,2-trifluoroethanol); TIS (triisopropylsilane); TPP(triphenylphosphine); and Trt (trityl[triphenylmethyl, (C₆H₅)₃C-]).

Other abbreviations used herein are as follows: 3-Pal(3-pyridylalanine); 5-Ava (5-amino valeric acid); chexcarbonyl or cHxCO(cyclohexylcarbonyl); Orn (ornithine); Tyr(Me) (methoxy analog oftyrosine); Cit (citruline); Dab (2,4-diaminobutyric acid); Hmp(2-hydroxy-3-mercaptopropionic acid); Hgn (homoglutamine); iBuCO(isovaleroyl), beta-Ala (beta alanine; 3-amino propionic acid); andisohArg (isohomoarginine).

II. Compounds

Provided herein are peptidic partial V1a receptor agonists having aparticular generic structural formula represented by formula (I) below:

wherein:

R¹ is selected from (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylNH,Ar¹-L¹- and unsubstituted or substituted cycloalkyl;

Ar¹-L¹- is selected from Ar¹—, Ar¹—CH₂—, Ar¹—CH₂CH₂—, Ar¹—O—, Ar¹—CH₂O—,Ar¹—NH— and Ar¹—CH₂NH—;

Ar¹ is unsubstituted aryl or substituted aryl;

R² is selected from hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy andhalogen;

R³ is selected from (C₁-C₆)alkyl, unsubstituted or substitutedcycloalkyl and Cy³-CH₂—;

Cy³- is unsubstituted or substituted aryl or unsubstituted orsubstituted cycloalkyl;

R⁴ is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, ((C₁-C₆)alkylene)-OR^(4a), —((C₁-C₆)alkylene)-NR^(4a)₂, —((C₁-C₆)alkylene)-S(C₁-C₆)alkyl, ((C₁-C₆)alkylene)C(═O)OR^(4a) ₂,—((C₁-C₆)alkylene)-C(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)-C(═NR^(4a))NR^(4a)₂, —((C₁-C₆)alkylene)-OC(═O)R^(4a), —((C₁-C₆)alkylene)-OC(═O)OR^(4a),—((C₁-C₆)alkylene)-OC(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)NR^(4a)C(═O)R^(4a),—((C₁-C₆)alkylene)NR^(4a)C(═O)OR^(4a),—((C₁-C₆)alkylene)NR^(4a)C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═NR^(4a))NR^(4a) ₂, Ar⁴ and—((C₁-C₆)alkylene)-Ar⁴;

each R^(4a) is independently selected from hydrogen and (C₁-C₆)alkyl;

Ar⁴ is selected from unsubstituted or substituted aryl and unsubstitutedor substituted heteroaryl;

R⁵ is selected from —((C₁-C₆)alkylene)-NR^(5a) ₂ and—((C₁-C₆)alkylene)-NR^(5a)C(═NR^(5a))NR^(5a) ₂;

each R^(5a) is independently selected from hydrogen and (C₁-C₆)alkyl;

Q is selected from the groups Q¹, Q², Q³ and Q⁴:

a and b denote the bonds attaching Q to the remainder of the molecule;

R⁶ is selected from hydrogen, (C₁-C₆)alkyl and —C(═NR^(6a))NR⁶⁹ ₂;

each R^(6a) is hydrogen or (C₁-C₆)alkyl;

R⁷ is selected from (C₁-C₆)alkyl, unsubstituted aryl, substituted aryl,unsubstituted cycloalkyl and substituted cycloalkyl;

R⁸ is selected from NH₂ and hydroxyl;

R⁹ is selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, ((C₁-C₆)alkylene)-OR^(9a),—((C₁-C₆)alkylene)-NR^(9a) ₂; —((C₁-C₆)alkylene)-SR^(9a),((C₁-C₆)alkylene)-C(═O)OR^(9a) ₂, —((C₁-C₆)alkylene)-C(═O)NR^(9a) ₂,—((C₁-C₆)alkylene)-C(═NR^(9a))NR^(9a) ₂,—((C₁-C₆)alkylene)-OC(═O)R^(9a), —((C₁-C₆)alkylene)-OC(═O)OR^(9a),—((C₁-C₆)alkylene)-OC(═O)NR⁹a₂, —((C₁-C₆)alkylene)-NR^(9a)C(═O)R^(9b),—((C₁-C₆)alkylene)-NR^(9a)C(═O)OR^(9a),—((C₁-C₆)alkylene)NR^(9a)C(═O)NR⁹a₂,—((C₁-C₆)alkylene)-NR^(9a)C(═NR^(9a))NR^(9a) ₂, Ar⁹ and—((C₁-C₆)alkylene)-Ar⁹;

each R^(9a) is independently selected from hydrogen and (C₁-C₆)alkyl;

each R^(9b) is independently selected from hydrogen and (C₁-C₁₀)alkyl;

Ar⁹ is selected from unsubstituted aryl, substituted aryl, unsubstitutedheteroaryl substituted heteroaryl;

R¹⁰ is selected from —((C₁-C₆)alkylene)-OR^(10a),—((C₁-C₆)alkylene)-C(═O)NR^(10a) ₂ and Ar¹⁰—CH₂—;

Ar¹⁰ is unsubstituted heteroaryl or substituted heteroaryl;

each R^(10a) is selected from hydrogen and (C₁-C₆)alkyl;

Ar is selected from aryl or substituted aryl;

each X is NH and each Y is C═O; or

each X is C═O and each Y is NH;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

o is 1 or 2;

p is 1, 2 or 3; and

r is 0, 1, 2, 3, 4, 5 or 6; provided that R⁹ is hydrogen if r is greaterthan one.

In some embodiments, R¹ can be (C₁-C₁₀)alkyl, e.g., (C₁-C₇)alkyl,(C₁-C₆)alkyl or (C₁-C₄)alkyl. R¹ can be, e.g., methyl, ethyl, n-propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, n-hexyl orn-heptyl. In some embodiments, R¹ can be (C₁-C₁₀)alkoxy, e.g.,(C₁-C₇)alkoxy or (C₁-C₆)alkoxy. R¹ can be, e.g., methoxy, ethoxy,n-propoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentoxy,n-hexyloxy or n-heptoxy. In some embodiments, R¹ can be(C₁-C₁₀)alkylamino, e.g., (C₁-C₇)alkylamino or (C₁-C₆)alkylamino R¹ canbe, e.g., methylamino, ethylamino, n-propylamino, isopropylamino,isobutylamino, sec-butylamino, tert-butylamino, neopentylamino,n-hexylamino or n-heptylamino.

In some embodiments, R¹ can be unsubstituted or substituted cycloalkyl,e.g., (C₃-C₁₂)cycloalkyl, e.g., (C₅-C₇)cycloalkyl or (C₆)cycloalkyl. R¹can be, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. In some embodiments, the cycloalkyl can be unsubstituted.In some embodiments, the cycloalkyl can be substituted. When R¹ issubstituted cycloalkyl, the cycloalkyl can be substituted, e.g., by 1, 2or 3 substituents independently selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, OR^(1a) andoxo, wherein each R^(1a) is independently selected from hydrogen and(C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, neopentyl or n-hexyl.

In some embodiments, R¹ can be represented by the formula Ar¹-L¹-,wherein Ar¹-L¹- can be Ar¹—, Ar¹—CH₂—, Ar¹—CH₂CH₂—, Ar¹—O—, Ar¹—CH₂O—,Ar¹—NH— or Ar¹—CH₂NH—. In some embodiments, Ar¹-L¹- can be Ar¹—CH₂—. Insome embodiments, Ar¹-L¹- can be Ar¹— or Ar¹—CH₂CH₂—. Ar¹ isunsubstituted aryl or substituted aryl, e.g., unsubstituted orsubstituted phenyl. When Ar¹ is substituted, the aryl, e.g., phenyl, canbe substituted, e.g., by 1, 2 or 3 substituents independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen,(C₁-C₆)haloalkyl, CN, NO₂, OR¹a, —NR^(1a) ₂ and NR^(1a)C(═O)R^(1a),wherein each R^(1a) is independently selected from hydrogen and(C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, neopentyl or n-hexyl.

In some embodiments, R¹ is (C₁-C₁₀)alkyl, (C₅-C₇)cycloalkyl or Ar¹—CH₂—.In some embodiments, R¹ is isobutyl, n-hexyl or cyclohexyl. In someembodiments, R¹ is benzyl.

In some embodiments, R² can be (C₁-C₆)alkyl, e.g., (C₁-C₄)alkyl. R² canbe, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, neopentyl or n-hexyl. In some embodiments, R² can behydroxy. In some embodiments, R² can be (C₁-C₆)alkoxy, e.g.,(C₁-C₄)alkoxy. R² can be, e.g., methoxy, ethoxy, n-propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentoxy or n-hexoxy. In someembodiments, R² can be methoxy. In some embodiments, R² can be halogen,e.g., fluoro, chloro or bromo.

In some embodiments, the amino acid having the carbon atom numbered 11as its α-carbon atom has D configuration, or, in other embodiments, Lconfiguration. The amino acid can be, e.g., D-O-methyl-tyrosine,D-p-chlorophenylalanine, L-O-methyl-tyrosine or L-p-chlorophenylalanine,

In some embodiments, R³ can be (C₁-C₆)alkyl, e.g., (C₁-C₄)alkyl. R³ canbe, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, neopentyl or n-hexyl.

In some embodiments, R³ can be unsubstituted or substituted cycloalkylor Cy³-CH₂—, wherein Cy³ is unsubstituted or substituted cycloalkyl. Thecycloalkyl can be, e.g., (C₃-C₁₂)cycloalkyl, e.g., (C₅-C₇)cycloalkyl or(C₆)cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl. In some embodiments, the cycloalkyl, alone or as part ofCy³-CH₂—, can be unsubstituted. In some embodiments, the cycloalkyl,alone or as part of Cy³-CH₂—, can be substituted. When substituted, thecycloalkyl, can be substituted, e.g., by 1, 2 or 3 substituentsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —OR^(3a) and oxo, whereineach R^(3a) is independently selected from hydrogen and (C₁-C₆)alkyl,e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, neopentyl or n-hexyl.

In some embodiments, R³ can be Cy³-CH₂—, wherein Cy³ is unsubstituted orsubstituted aryl (Ar³). Ar³ is unsubstituted aryl or substituted aryl,e.g., unsubstituted or substituted phenyl. In some embodiments, when Ar³is substituted, the aryl, e.g., phenyl, can be substituted, e.g., by 1,2 or 3 substituents independently selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, CN, NO₂,—OR^(3a), —NR^(3a) ₂ and NR^(3a)C(═O)R^(3a), wherein each R^(3a) isindependently selected from hydrogen and (C₁-C₆)alkyl, e.g., methyl,ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentylor n-hexyl. In some embodiments, the substituted aryl, e.g., phenyl, ishalo-substituted, e.g., mono-halo-substituted.

In some embodiments, R³ is selected from (C₁-C₆)alkyl and Ar³— CH₂—,wherein Ar³— is unsubstituted or substituted aryl. In some embodiments,Ar³ is unsubstituted aryl or halo-substituted aryl. In some embodiments,Ar³ is phenyl. In some embodiments, Ar³ can be phenyl or phenylsubstituted with hydroxy, alkoxy or halogen, e.g., 4-chlorophenyl. Insome embodiments, R³ is selected from (C₁-C₆)alkyl and Ar³—CH₂—, whereinAr³ is phenyl or halo-substituted phenyl. In some embodiments, R³ iss-butyl, neopentyl, benzyl or 4-chlorobenzyl.

In some embodiments, the amino acid having the carbon atom numbered 12as its α-carbon atom (i.e., with R³ as its side-chain) can be, e.g.,alanine, leucine, isoleucine, valine, phenylalanine,4-chlorophenylalanine or tyrosine.

In some embodiments, R⁴ can be (C₁-C₁₀)alkyl, e.g., (C₁-C₇)alkyl or(C₁-C₆)alkyl. R⁴ can be, e.g., methyl, ethyl, n-propyl, isopropyl,isobutyl, sec-butyl, tert-butyl, neopentyl, n-hexyl or n-heptyl.

In some embodiments, R⁴ can be —((C₁-C₆)alkylene)-OR^(4a),—((C₁-C₆)alkylene)-OR^(4a), ((C₁-C₆)alkylene)-NR^(4a) ₂,((C₁-C₆)alkylene)-S(C₁-C₆)alkyl, —((C₁-C₆)alkylene)-C(═O)OR^(4a) ₂,—((C₁-C₆)alkylene)-C(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)-C(═NR^(4a))NR^(4a)₂, ((C₁-C₆)alkylene)-OC(═O)R^(4a), —((C₁-C₆)alkylene)-OC(═O)OR^(4a),((C₁-C₆)alkylene)-OC(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═O)R^(4a),((C₁-C₆)alkylene)-NR^(4a)C(═O)OR^(4a),—((C₁-C₆)alkylene)-NR^(4a)C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═NR^(4a))NR^(4a) ₂ or—((C₁-C₆)alkylene)-Ar⁴, wherein R^(4a) is hydrogen or (C₁-C₆)alkyl,e.g., methyl. The (C₁-C₆)alkylene chain can have 1, 2, 3, 4, 5 or 6carbon atoms and can be composed of methylene groups. For example, R⁴can be of the formula —(CH₂)₁₋₆—OR^(4a), —(CH₂)₁₋₆—NR^(4a) ₂,—(CH₂)₁₋₆—C(═O)NR^(4a) ₂, —(CH₂)₁₋₆—NR^(4a)C(═O)NR^(4a) ₂,—(CH₂)₁₋₆—NR^(4a)C(═NR^(4a))NR^(4a) ₂ and —(CH₂)₁₋₆-Ar⁴, e.g.,—(CH₂)—OR^(4a), —(CH₂)₂₋₄—NR^(4a) ₂, —(CH₂)₁₋₃—C(═O)NR^(4a) ₂,—(CH₂)₂₋₄—NR^(4a)C(═O)NR^(4a) ₂, —(CH₂)₂₋₄—NR^(4a)C(═NR^(4a))NR^(4a) ₂and —(CH₂)—Ar⁴.

In some embodiments, R⁴ is (C₁-C₆)alkyl, —((C₁-C₆)alkylene)-OR^(4a),—((C₁-C₆)alkylene)-NR^(4a) ₂, ((C₁-C₆)alkylene)-C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═NR^(4a))NR^(4a) ₂ or—((C₁-C₆)alkylene)-Ar⁴. In some embodiments, R⁴ is selected from(C₁-C₆)alkyl, —(CH₂)₁₋₆—OR^(4a), —(CH₂)₁₋₆—NR^(4a) ₂,—(CH₂)₁₋₆—C(═O)NR^(4a) ₂, —(CH₂)₁₋₆—NR^(4a)C(═O)NR^(4a) ₂,—(CH₂)₁₋₆—NR^(4a)C(═NR^(4a))NR^(4a) ₂ and —(CH₂)₁₋₆-Ar⁴. In someembodiments, R⁴ is selected from (C₁-C₆)alkyl, —(CH₂)—OR^(4a),—(CH₂)₂₋₄—NR^(4a) ₂, —(CH₂)₁₋₃—C(—O)NR^(4a) ₂,—(CH₂)₂₋₄—NR^(4a)C(═O)NR^(4a) ₂, —(CH₂)₂₋₄—NR^(4a)C(═NR^(4a))NR^(4a) ₂and —(CH₂)—Ar⁴.

In R⁴, each R^(4a) can be, independently, hydrogen or (C₁-C₆)alkyl,e.g., methyl. In some embodiments, each R^(4a) is independently hydrogenor methyl. In some embodiments, each R^(4a) is hydrogen. In someembodiments, when R⁴ has more than one R^(4a) group all of the R^(4a)groups are hydrogen, or only one of the R^(4a) groups is (C₁-C₆)alkyl,e.g., methyl.

In R⁴, and embodiments thereof, Ar⁴ can be unsubstituted aryl orsubstituted aryl, e.g., unsubstituted or substituted phenyl orunsubstituted heteroaryl or substituted heteroaryl. When Ar⁴ issubstituted, the aryl, e.g., phenyl, or heteroaryl can be substituted,e.g., by 1, 2 or 3 substituents independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl,CN, NO₂, 0R^(4b), —NR^(4b) ₂ and NR^(4b)C(═O)R^(4b), wherein each R^(4b)is independently selected from hydrogen and (C₁-C₆)alkyl, e.g., methyl,ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentylor n-hexyl. In some embodiments, Ar⁴ is heteroaryl, e.g., unsubstitutedheteroaryl, e.g., pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazolyl,isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, indolyl,indolinyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl,benzoxazolyl, benzthiazolyl and benzimidazolyl. In some embodiments, Ar⁴is imidazolyl, e.g., 1H-imidazol-4-yl or indolyl, e.g., indol-3-yl.

In some embodiments, R⁴ is methyl, isobutyl, —CH₂OH, —(CH₂)₂—NH₂,—(CH₂)3-NH₂, —(CH₂)₄—NH₂, —(CH₂)₂—C(═O)NH₂, —(CH₂)₃—NHC(═NH)NH₂,—(CH₂)₃—NHC(═O)NH₂ or —CH₂(1H-imidazol-4-yl).

In some embodiments, the amino acid having the carbon atom numbered 15as its α-carbon atom (i.e., with R⁴ as its side-chain) can be, e.g.,alanine, arginine, asparagine, citrulline, 2,4-diaminobutyric acid,glutamine, histidine, isoleucine, leucine, lysine, ornithine,phenylalanine, serine, tryptophan or valine.

R⁵ is —((C₁-C₆)alkylene)-NR^(5a) ₂ or—((C₁-C₆)alkylene)-NR^(5a)C(═NR^(5a))NR^(5a) ₂; wherein each R^(5a) isindependently hydrogen or (C₁-C₆)alkyl, e.g., methyl. The(C₁-C₆)alkylene chain can have 1, 2, 3, 4, 5 or 6 carbon atoms and canbe composed of methylene groups. For example, R⁵ can be of the formula—(CH₂)₁₋₆—NR^(5a) ₂, or of the formula—(CH₂)₁₋₆NR^(5a)C(═NR^(5a))NR^(5a) ₂. In some embodiments, R⁵ is—(CH₂)₂₄—NR^(5a) ₂ or —(CH₂)₂₋₄NR^(5a)C(═NR^(5a))NR^(5a) ₂. In someembodiments, each R^(5a) is independently hydrogen or methyl. In someembodiments, each R^(5a) is hydrogen. In some embodiments, when R⁵ is—((C₁-C₆)alkylene)-NR^(5a)C(═NR^(5a))NR^(5a) ₂, all of the R^(5a) groupsare hydrogen, or only one of the R^(5a) groups is (C₁-C₆)alkyl, e.g.,methyl.

In some embodiments, R⁵ is —(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₄—NH₂ or—(CH₂)₃—NHC(═NH)NH₂. In some embodiments, R⁵ is —(CH₂)₃—NHC(═NH)NH₂.

In some embodiments, therefore, the amino acid having the carbon atomnumbered 17 as its α-carbon atom (i.e., with R⁵ as its side-chain) canbe, e.g., alanine, arginine, 2,4-diaminobutyric acid, lysine orornithine.

In some embodiments, R⁷ can be (C₁-C₆)alkyl, e.g., (C₁-C₄)alkyl. R⁷ canbe, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, neopentyl or n-hexyl.

In some embodiments, R⁷ can be unsubstituted or substituted cycloalkyl,e.g., (C₃-C₁₂)cycloalkyl, e.g., (C₅-C₇)cycloalkyl or (C₆)cycloalkyl. R⁷can be, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. In some embodiments, the cycloalkyl can be unsubstituted.In some embodiments, the cycloalkyl can be substituted. When R⁷ issubstituted cycloalkyl, the cycloalkyl can be substituted, e.g., by 1, 2or 3 substituents independently selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —OR^(7a) andoxo, wherein each R^(7a) is independently selected from hydrogen and(C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, neopentyl or n-hexyl.

In some embodiments, R⁷ can be unsubstituted or substituted aryl (Ar⁷),e.g., unsubstituted or substituted phenyl. When the aryl is substituted,the aryl, e.g., phenyl, can be substituted, e.g., by 1, 2 or 3substituents independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, CN, NO₂, —OR^(7a), —NR^(7a) ₂and —NR^(7a)C(═O)R^(7a), wherein each R^(7a) is independently selectedfrom hydrogen and (C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl or n-hexyl.

In some embodiments, R⁷ is (C₁-C₆)alkyl or (C₄-C₇)cycloalkyl. In someembodiments, R⁷ is (C₁-C₆)alkyl. In some embodiments, R⁷ is s-butyl.

In some embodiments, therefore, the amino acid having the carbon atomnumbered 3 as its α-carbon atom (i.e., with R⁷ as its side-chain) canbe, e.g., alanine, leucine, isoleucine or valine.

R⁸ can be NH₂ or OH. In some embodiments, R⁸ is —NH₂. In someembodiments, R⁸ is —OH. In some embodiments, therefore, the acid havingthe carbon atom numbered 1 as its α-carbon atom can be, e.g., cysteineor (R)-2-hydroxy-3-mercaptopropanoic acid.

In some embodiments, R¹⁰ is selected from —((C₁-C₆)alkylene)-OR^(10a)and —((C₁-C₆)alkylene)-C(═O)NR^(10a) ₂. The (C₁-C₆)alkylene chains canhave 1, 2, 3, 4, 5 or 6 carbon atoms and can be composed of methylenegroups. For example, R¹⁰ can be of the formula —(CH₂)₁₋₆—C(═O)NR^(10a)₂, e.g., —(CH₂)₁₋₆—C(═O)NR^(10a) ₂. Each R^(10a) is independentlyselected from hydrogen and (C₁-C₆)alkyl, e.g., methyl. In someembodiments, each R^(10a) is hydrogen.

In some embodiments, R¹⁰ is Ar¹⁰—CH₂—. In some embodiments, Ar¹⁰ isunsubstituted heteroaryl. In some embodiments, Ar¹⁰ is substitutedheteroaryl. In some embodiments, when Ar¹⁰ is substituted, theheteroaryl is substituted, e.g., by 1, 2 or 3 substituents selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl,—CN, —NO₂, —OR^(10b), —NR^(10b) ₂ and —NR^(10b)C(═O)R^(10b). EachR^(10b) is independently selected from hydrogen and (C₁-C₆)alkyl, e.g.,methyl. In some embodiments, Ar¹⁰ is heteroaryl, e.g., unsubstitutedheteroaryl, and can be, e.g., pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl,oxadiazolyl, indolyl, indolinyl, quinolyl, isoquinolyl, benzofuryl,benzothienyl, benzoxazolyl, benzthiazolyl or benzimidazolyl. In someembodiments, Ar¹⁰ is pyridyl, e.g., 3-pyridyl.

In some embodiments, R¹⁰ is 1-hydroxyethyl, —(CH₂)₂—C(═O)NH₂ or3-pyridyl-CH₂—. In some embodiments, R¹⁰ is —(CH₂)₂—C(═O)NH₂.

In some embodiments, therefore, the amino acid having the carbon atomnumbered 13 as its α-carbon atom (i.e., with R¹⁰ as its side-chain) canbe, e.g., asparagine, glutamine, threonine or 3-pyridylalanine.

Ar can be unsubstituted or substituted aryl, e.g., unsubstituted orsubstituted phenyl. When Ar is substituted, the aryl, e.g., phenyl, canbe substituted, e.g., by 1, 2 or 3 substituents independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen,(C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(Ar), —NR^(Ar) ₂ and—NR^(Ar)C(═O)R^(Ar), wherein each R^(Ar) is independently selected fromhydrogen and (C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl, isopropyl,isobutyl, sec-butyl, tert-butyl, neopentyl or n-hexyl. In someembodiments, Ar is phenyl or substituted phenyl. In some embodiments, Aris phenyl.

In some embodiments, therefore, the amino acid having the carbon atomnumbered 2 as its α-carbon atom (i.e., with —CH₂Ar as its side-chain)can be, e.g., phenylalanine.

In some embodiments, each X is NH and each Y is C═O.

In other embodiments, each X is C═O and each Y is NH.

m can be 0, 1, 2, 3, 4 or 5. In some embodiments, m is 0, 1, 2, 3 or 4.In some embodiments, m is 1. In some embodiments, m is 3.

o can be 1 or 2. In some embodiments, o is 1. In some embodiments, o is2.

p is 1, 2 or 3. In some embodiments, p is 1. In some embodiments, p is2. In some embodiments, p is 3.

In some embodiments, therefore, the amino acid having the carbon atomnumbered 4 as its α-carbon atom (i.e., with (CH₂)_(p)(C═O)NH₂ as itsside-chain) can be, e.g., asparagine, glutamine or homoglutamine

In some embodiments, Q is Q¹. n can be any of 0, 1, 2, 3 or 4. r can beany of 0, 1, 2, 3, 4, 5 or 6. In some embodiments, when Q is Q¹, n is 1.In some embodiments, when Q is Q¹, n is 2. In some embodiments, when Qis Q¹, n is 3. In some embodiments, when Q is Q¹, R⁶ is hydrogen or—C(═NR^(6a))NR^(6a) ₂. Each R^(6a) is independently hydrogen or(C₁-C₆)alkyl, e.g., methyl. In some embodiments, each R^(6a) is hydrogenor methyl. In some embodiments, at least two of R^(6a) are hydrogen. Insome embodiments, each R^(6a) is hydrogen. In some embodiments, when Qis Q¹, R⁶ is hydrogen or —C(═NH)NH₂.

In some embodiments, when Q is Q¹, Q¹ is^(a)—NH(CH₂)₄CH(NH₂)—C(═O)—^(b), ^(a)—NH(CH₂)₄CH(NHC(═NH)NH₂)—C(═O)—^(b)or ^(a)—C(═O)(CH₂)₂CH(NH₂)—C(═O)—^(b). In some embodiments, when Q isQ¹, Q¹ is ^(a)—NH(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)—NH(CH₂)₄C^((S))H(NHC(═NH)NH₂)—C(═O)—^(b) or^(a)-C(═O)(CH₂)₂C(H(NH₂)—C(═O)—^(b) or^(a)-C(═O)(CH₂)₂C^((R))H(NH₂)—C(═O)—^(b).

In some embodiments, Q is Q². n can be any of 0, 1, 2, 3 or 4. In someembodiments, when Q is Q², n is 0. In some embodiments, when Q is Q², nis 1. In some embodiments, when Q is Q², n is 2. In some embodiments,when Q is Q², n is 3.

In some embodiments, when Q is Q², Q² is ^(a)—NH(CH₂)₄-^(b),^(a)—NH(CH₂)₅-^(b), ^(a)—NH(CH₂)₆-^(b), ^(a)—C(═O)—(CH₂)₃—^(b) or^(a)-C(═O)—(CH₂)₅—^(b).

In some embodiments, Q is Q³. n can be any of 0, 1, 2, 3 or 4. r can beany of 0, 1, 2, 3, 4, 5 or 6. In some embodiments, when Q is Q³, n is 3.In some embodiments, when Q is Q³, r is 0. In some embodiments, when Qis Q³, r is 3. In some embodiments, when Q is Q³, R⁶ is hydrogen or—C(═NR^(6a))NR^(6a) ₂. Each R^(6a) is independently hydrogen or(C₁-C₆)alkyl, e.g., methyl. In some embodiments, each R^(6a) is hydrogenor methyl. In some embodiments, at least two of R^(6a) are hydrogen. Insome embodiments, each R^(6a) is hydrogen. In some embodiments, when Qis Q³, R⁶ is hydrogen or —C(═NH)NH₂.

In Q³, in some embodiments, R⁹ can be (C₁-C₆)alkyl. e.g., (C₁-C₇)alkylor (C₁-C₆)alkyl. R⁹ can be, e.g., methyl, ethyl, n-propyl, isopropyl,isobutyl, sec-butyl, tert-butyl, neopentyl, n-hexyl or n-heptyl.

In some embodiments, R⁹ can be (C₁-C₆)haloalkyl,—((C₁-C₆)alkylene)-OR^(9a), —((C₁-C₆)alkylene)-NR^(9a) ₂,—((C₁-C₆)alkylene)-SR^(9a), ((C₁-C₆)alkylene)-C(═O)OR^(9a) ₂,—((C₁-C₆)alkylene)-C(═O)NR^(9a) ₂, —((C₁-C₆)alkylene)-C(═NR^(9a))NR^(9a)₂, —((C₁-C₆)alkylene)-OC(═O)R^(9a), —((C₁-C₆)alkylene)-OC(═O)OR^(9a),—((C₁-C₆)alkylene)-OC(═O)NR⁹a₂, —((C₁-C₆)alkylene)-NR^(9a)C(═O)R^(9b),—((C₁-C₆)alkylene)-NR^(9a)C(═O)OR^(9a),—((C₁-C₆)alkylene)-NR^(9a)C(═O)NR⁹a₂ or—((C₁-C₆)alkylene)-NR^(9a)C(═NR^(9a))NR^(9a) ₂. The (C₁-C₆)alkylenechains can have 1, 2, 3, 4, 5 or 6 carbon atoms and can be composed ofmethylene groups. For example, R⁹ can be of the formula—(CH₂)₁₋₆—OR^(9a), —(CH₂)₁₆—NR^(9a) ₂, —(CH₂)₁₆—SR^(9a),—(CH₂)₁₋₆—C(═O)OR^(9a) ₂, —(CH₂)₁₋₆—C(═O)NR^(9a) ₂,—(CH₂)₁₋₆—C(═NR^(9a))NR^(9a) ₂, —(CH₂)₁₋₆—OC(═O)R^(9b),—(CH₂)₁₋₆—OC(═O)OR^(9a), —(CH₂)₁₋₆—OC(═O)NR^(9a) ₂,—(CH₂)₁₋₆—NR^(9a)C(═O)R^(9b), —(CH₂)₁₋₆—NR^(9a)C(═O)OR^(9a),—(CH₂)₁₋₆—NR^(9a)C(═O)NR⁹a₂ or —(CH₂)₁₋₆—NR^(9a)C(═NR⁹a)NR⁹a₂. In someembodiments, R⁹ can be —((C₁-C₆)alkylene)-C(═O)NR⁹a₂ or—((C₁-C₆)alkylene)-NR^(9a)C(═O)R^(9b), e.g., —(CH₂)₁₋₆—NR⁹a₂ or—(CH₂)₁₋₆—NR^(9a)C(═O)R^(9b). Each R^(9a) is independently selected fromhydrogen and (C₁-C₆)alkyl, e.g., methyl. In some embodiments, each R⁹ais hydrogen. Each R^(9b) is independently selected from hydrogen and(C₁-C₁₀)alkyl, e.g., (C₁-C₆)alkyl, e.g., methyl or n-hexyl. In someembodiments, R⁹ can be, e.g., —CH₂—NH₂, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂ or—(CH₂)₄—NH₂, —CH₂—NHC(═O)R^(9b), —(CH₂)₂—NHC(═O)R^(9b),—(CH₂)₃—NHC(═O)R^(9b) or —(CH₂)₄—NHC(═O)R^(9b); or each formula R^(9b)can be, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl orn-hexyl. In some embodiments, R⁹ can be, e.g., —(CH₂)₄—NH₂, —(CH₂)₄—NHAcor —(CH₂)₄—NHheptanoyl.

In some embodiments, R⁹ can be Ar⁹ or —((C₁-C₆)alkylene)-Ar⁹. The(C₁-C₆)alkylene chains can have 1, 2, 3, 4, 5 or 6 carbon atoms and canbe composed of methylene groups. For example, R⁹ can be of the formula—(CH₂)₁₋₆-Ar⁹, e.g., —CH₂—Ar⁹. Ar⁹ can be unsubstituted or substitutedaryl, e.g. phenyl, or unsubstituted or substituted heteroaryl. In someembodiments, when Ar⁹ is substituted, the aryl, e.g., phenyl, orheteroaryl can be substituted, e.g., by 1, 2 or 3 substituentsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(9c), —NR^(9c)₂ and —NR^(9c)C(═O)R^(9c), wherein each R^(9c) is independently selectedfrom hydrogen and (C₁-C₆)alkyl, e.g., methyl, ethyl, n-propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl or n-hexyl. Insome embodiments, when Ar⁹ is heteroaryl, e.g., unsubstitutedheteroaryl, Ar⁹ can be, e.g., pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl,oxadiazolyl, indolyl, indolinyl, quinolyl, isoquinolyl, benzofuryl,benzothienyl, benzoxazolyl, benzthiazolyl or benzimidazolyl.

In some embodiments, Q³ is^(a)—NH(CH₂)₄—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b),^(a)—NHCH((CH₂)₄NH₂)—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b),^(a)—NHCH((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b) or^(a)-NHCH((CH₂)₄NHHeptanoyl)-C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b). In someembodiments, Q³ is^(a)-NH(CH₂)₄—C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NHC(H((CH₂)₄NH₂)—C(═O)—NH—(CH₂)₄C(H(NH₂)—C(═O)—^(b),^(a)-NHC(H((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NHC(H((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄C^((R))H(NH₂)—C(═O)—^(b) or^(a)-NHC(H((CH₂)₄NHHeptanoyl)-C(═O)—NH—(CH₂)₄C(H(NH₂)—C(═O)—^(b).

In some embodiments, Q is Q⁴. n can be any of 0, 1, 2, 3 or 4. r can beany of 0, 1, 2, 3, 4, 5 or 6. In some embodiments, when Q is Q⁴, n is 1.In some embodiments, when Q is Q⁴, n is 2. In some embodiments, when Qis Q⁴, n is 3. In some embodiments, when Q is Q⁴, r is 1. In someembodiments, when Q is Q⁴, r is 2. In some embodiments, when Q is Q⁴, ris 3.

In some embodiments, when Q is Q⁴, Q⁴ can be^(a)_NH—(CH₂)₂—C(═O)—NH—(CH₂)₅-^(b),^(a)-NH—(CH₂)₄—C(═O)—NH—(CH₂)₆-^(b),^(a)-C(═O)—(CH₂)₂—C(═O)—NH—(CH₂)₆-^(b) or^(a)-C(═O)—(CH₂)₃—C(═O)—NH—(CH₂)₄-^(b).

The following peptidic partial V1a agonist compounds can illustrate thegeneric structure provided in formula (I). In the following sequences,with reference to structural formula (1), the bottom line lists aminoacids of the peptide fragment containing the carbon atoms that arelabeled 10-18 in formula (I) and the bottom line lists amino acids ofthe peptide fragment containing carbon atoms that are labeled 1-9 informula (I), together with the group Q. The link between Q and thepeptide fragment containing carbons atoms 1-9 (i.e., bond “b” in formula(I)) is indicated by a vertical line.

The following are molecular structures of particular exemplifiedcompounds.

III. Synthesis

In general, the methods of peptide synthesis are applicable to thesynthesis of the compounds of formula (I). Methods of peptide synthesisare well-developed in the art and typically use protected amino acids,typically protected with a carbamate group (e.g., t-butyloxycarbonyl(“BOC”) or fluorenylmethoxycarbonyl (Fmoc). In a typical process, theprotected amino acid is coupled to a free amino group of a growingpeptide chain to give a peptide extended by an additional amino acidunit. The amino group of the new terminal amino acid of the growingpeptide chain is then deprotected, and is available for further couplingreactions. Due to the well-developed methods available for peptidesynthesis, methods that are suitable for synthesis of the compounds offormula (I) will be apparent to one skilled in the art from thestructure of such compounds. Syntheses of particular compounds aredescribed in the Examples, and the methods described can be adapted toadditional compounds within the scope of formula (I), e.g., bysubstituting appropriate amino acid derivatives as necessary.

Due to the biological importance of peptides and peptide analogues, awide variety of amino acids is commercially available or known in theart. In addition, numerous methods of making such compounds are known inthe art. Therefore, the amino acids (as well as other intermediates)required to make compounds of formula (I) are commercially available,known in the art, or may be made by methods known in the art.

Methods of synthesizing amino acids and peptides are described, e.g.,by: Benoiton, Chemistry of Peptide Synthesis, CRC Press, 2006; Hughes,et al., Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 1,Origins and Synthesis of Amino Acids, Wiley-VCH 2009; Hughes, et al.,Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 2.Modified Amino Acids, Organocatalysis and Enzymes; Wiley-VCH 2010;Hughes, et al., Amino Acids, Peptides and Proteins in Organic ChemistryVol. 3: Building Blocks, Catalysis and Coupling Chemistry, Wiley-VCH2011; Hughes, et al., Amino Acids, Peptides and Proteins in OrganicChemistry, Vol. 4: Amino Acids, Peptides and Proteins in OrganicChemistry, Protection Reactions, Medicinal Chemistry, CombinatorialSynthesis, Wiley-VCH 2011; Amino Acids, Peptides and Proteins in OrganicChemistry, Vol. 5: Amino Acids, Peptides and Proteins in OrganicChemistry, Analysis and Function of Amino Acids and Peptides, Wiley-VCH2011; Howl, et al., Peptide Synthesis and Applications (Methods inMolecular Biology Vol. 298), Humana Press, 2010; Jones, Amino Acid andPeptide Synthesis, 2nd edn., Oxford University Press, 2002; Jones, TheChemical Synthesis of Peptides (International Series of Monographs onChemistry), Oxford University Press, 1994; Pennington, et al., PeptideSynthesis Protocols (Methods in Molecular Biology Vol. 35), HumanaPress, 1994; Sewald, et al., Peptides: Chemistry and Biology, Wiley-VCH,2009; Williams, et al., Chemical Approaches to the synthesis of Peptidesand Proteins (New Directions in Organic & Biological Chemistry), CRCPress 1997.

IV. Formulation and Administration

Compositions provided herein may comprise the partial V1a receptoragonists of formula (I) described herein, their salts, or any of theembodiments thereof. The compounds provided herein are particularlysoluble at physiological pHs (e.g., about 6.8 to about 7.4) and can beprepared as relatively concentrated solutions for administration,particularly for subcutaneous injection. These compounds arewell-tolerated in the body and do not tend to gel when administeredsubcutaneously at effective concentrations.

Generally, pharmaceutical compositions including such compounds and asuitable pharmaceutically acceptable excipient can be administeredparenterally, e.g., intravenously, intraperitoneally, intramuscularly,subcutaneously, or the like. The pharmaceutical compositions willusually contain an effective amount of the compound in conjunction witha conventional, pharmaceutically-acceptable carrier or diluent. Usually,the dosage will be from about 1 micrograms to about 2.5 milligrams ofthe peptide per kilogram of the body weight of the host when givenintravenously. The nature of these compounds may permit effective oraladministration; however, oral dosages might be higher.

For parenteral administration, the compound may be formulated, e.g., asa sterile solution or suspension. The compounds may be formulated, e.g.,as a sterile aqueous preparation that may be isotonic with the blood ofthe recipient. An aqueous preparation may be formulated, e.g., accordingto known methods using suitable dispersing agents, wetting agents,and/or suspending agents. Water, Ringer's solution, and isotonic sodiumchloride solution are examples of suitable diluents. Sterile, fixed oilsmay be employed as a solvent or suspending system. Bland fixed oils,including synthetic mono- or di-glycerides, and fatty acids, such asoleic acid, may be used.

The amount of compound or composition to be administered will bedetermined by the responsible physician, taking into consideration allthe relevant factors. In a preferred embodiment, the amount of compoundor composition administered in each injection will be between about0.001 mg to about 2.5 mg per Kg of body weight per day, with about 0.2mg/Kg/day usually being sufficient.

The compounds, and compositions containing the compounds, could be givenintravenously or subcutaneously, e.g., once, or chronically, to increasesystemic vascular resistance and/or reduce splanchnic blood flow totreat any of the indications. In some embodiments, the compounds areadministered by intravenous injection. A course of treatment may involvea single injection or repeated injections.

In general, dosing frequency can range from as infrequently as severaltimes a week, up to several times per day. In general, duration oftherapy can range from as short as about a few days or a week, up tocontinuously. When treatment of the patient includes paracentesis, thecourse of treatment can comprise an injection immediately before thestart of paracentesis and one or more (such as two or three) injectionsfollowing the paracentesis and at least one, such as two, injectionsafterwards. The injections may be separated by a period of a few hours,such as a period of between 4 and 12 h, more preferably between 6 and 10h. A course of treatment can comprise an injection before the start ofparacentesis and follow-up injections 8 and 16 h later.

The compounds provided herein are often administered in the form ofpharmaceutically acceptable, nontoxic salts, such as acid additionsalts, or of metal complexes, e.g., with zinc, barium, calcium,magnesium, aluminum, or the like (which are considered as addition saltsfor purposes of this application), or of combinations of the two.Illustrative of such acid addition salts are hydrochloride,hydrobromide, sulfate, phosphate, nitrate, oxalate, fumarate, gluconate,tannate, pamoate, maleate, acetate, citrate, benzoate, succinate,alginate, malate, ascorbate, tartrate, and the like.

V. Methods of Use

Also provided herein are methods of treatment and methods of using thecompounds and compositions described and provided herein, e.g., for themanufacture of medicinal products for therapeutic effect. The compounds,and compositions containing the compounds, are useful for treatment of,e.g., complications of cirrhosis, including bacterial peritonitis, HRS2and refractory ascites.

Provided herein are compounds that have a reduced maximal efficacy atthe V1a receptor such that the risk of excessive vasoconstriction issignificantly reduced. The compounds are also useful, e.g., fortreatment to increase blood pressure. These compounds are especiallyuseful in the treatment of conditions where a modest increase in bloodpressure is desirable, such as shock of hypovolemic (e.g., hemorrhagic)or vasodilatory (e.g., septic) origin, bleeding esophageal varices(BEV), hepatorenal syndrome (HRS), including type I and type IIheptoarenal syndrome, cardiopulmonary resuscitation andanesthesia-induced hypotension. These compounds are also especiallyuseful in the treatment of complications arising from cirrhosis,including spontaneous bacterial peritonitis, type II heptoarenalsyndrome (HRS2) and refractory ascites. Refractory ascites refers to aninability to mobilize ascitic fluid and can be diagnosed by thefollowing criteria: lack of response to maximal doses of diuretic for atleast one week; diuretic-induced complications in the absence of otherprecipitating factors; early recurrence of ascites within 4 weeks offluid mobilization; persistent ascites despite sodium restriction; meanweight loss less than 0.8 kg over 4 days despite maximal doses ofdiuretics; and urinary sodium excretion less than sodium intake(Siqueira, et al., Gastroenterol. Hepatol., (N.Y.), 2009, 5(9),647-656.)

The compounds described herein will also have clinical use in thetreatment of orthostatic hypotension, paracentesis-induced circulatorydysfunction, acute hemorrhage, intra-operative blood loss and blood lossassociated with burn debridement and blood loss associated withepistaxis.

Other conditions that can be treated with the compounds described hereininclude: hypertensive gastropathy bleeding; sepsis; severe sepsis;septic shock; hypotension, including prolonged and severe hypotension,and orthostatic hypotension and intradialytic hypotension; cardiacarrest; trauma-related blood loss; vasodilatory shock induced bycardio-pulmonary bypass; milrinone-induced vasodilatory shock incongestive heart failure; type I hepatorenal syndrome; type IIhepatorenal syndrome; anaphylactic shock; cardiovascular instabilityinduced by brain death; acute respiratory distress syndrome; acute lunginjury; shock induced by metformin intoxication; shock induced bymitochondrial disease; shock induced by cyanide poisoning; shock inducedby vascular leak syndrome induced by interleukin-2, another cytokine,denileukin diftitox or another immunotoxin, or by ovarianhyperstimulation syndrome; hypotension induced by end-stage renaldisease; inflammatory bowel disease; reperfusion injury; infantrespiratory distress syndrome; severe acute respiratory syndrome;ascites; vasodepressor syncope; vasovagal syncope, e.g., posturalhypotension with syncope, or neurocardiogenic syncope; toxic shocksyndrome; and idiopathic systemic capillary leak syndrome (Clarkson'sdisease).

These compounds also display an improved therapeutic index over therapyinvolving, e.g., terlipressin.

Examples 1. General Methods

Amino acid derivatives were purchased from commercial providers (Bachem,EMD Biosciences and Peptides International). Resins were purchased fromcommercial suppliers (PCAS BioMatrix Inc. and EMD Biosciences). Alladditional reagents, chemicals and solvents were purchased fromSigma-Aldrich and VWR.

Most of the compounds herein were synthesized by standard methods insolid phase peptide chemistry utilizing Fmoc methodology. The peptideswere assembled either manually, automatically using a ProteinTechnologies Tribute Peptide Synthesizer or by combination of manual andautomatic syntheses. If more convenient the compounds were assembledmanually using combination of Boc and Fmoc strategies (e.g., compounds26, 29).

Preparative HPLC was performed on a Waters Prep LC System using aPrepPack cartridge Delta-Pack C18, 300 Å, 15 μm, 47×300 mm at a flowrate of 100 mL/min and/or on a Phenomenex Luna C18 column, 100 Å, 5 μm,30×100 mm at a flow rate of 40 mL/min. Analytical reverse phase HPLC wasperformed on an Agilent Technologies 1200rr series liquid chromatographusing an Agilent Zorbax C18 column, 1.8 μm, 4.6×110 mm at a flow rate of1.5 mL/min. Final compound analyses were performed on an AgilentTechnologies 1200 Series chromatograph by reverse phase HPLC on aPhenomenex Gemini 110 Å C18 column, 3 μm, 2×150 mm at a flow rate of 0.3mL/min. Mass spectra were recorded on a MAT Finningan LCQ electrospraymass spectrometer. Unless stated otherwise, all reactions were performedat room temperature. The following standard reference literatureprovides further guidance on general experimental set up, as well as onthe availability of required starting material and reagents: Kates, etal., Solid Phase Synthesis: A Practical Guide, Marcel Dekker, New York,Basel, 2000; Greene, et al., Protective Groups in Organic Synthesis,John Wiley Sons Inc., 2^(nd) Edition, 1991; Stewart, et al., Solid PhaseSynthesis, Pierce Chemical Company, 1984; Bisello, et al., J. Biol.Chem., 1998, 273, 22498-22505; Merrifield, J. Am. Chem. Soc., 1963, 85,2149-2154; and Chang, et al., Fmoc Solid Phase Peptide Synthesis: aPractical Approach, Oxford University Press, Oxford, 2000.H-Rink-ChemMatrix resin (PCAS BioMatrix Inc., St-Jean-sur-Richelieu,Canada) was used as starting material for automatic synthesis andFmoc-Rink-AM resin (EMD Biosciences, San Diego, Calif.) was used formanual synthesis.

The following protecting groups were utilized to protect the given aminoacid side chain functional groups: Pbf(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl) for Arg; tBu(t-butyl) for Glu, Asp, Ser, Thr and Tyr; Trt (trityl) for Cys, His, Glnand Asn; Boc (t-butoxycarbonyl) group for Dab, Orn and Lys. The Mtt(4-methyltrityl) or ivDde(1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)3-methylbutyl) protectinggroups were used in the side chain of the diamino acid residue of alphaamino acid 8 to provide an additional level of orthogonality forbranching.

Peptides were prepared on solid support starting with residues 1-9 ofthe peptide shown in Formula (I), followed by the removal of theposition 8 side chain orthogonal protecting group and the addition ofthe alpha amino acid 10-18 containing peptide fragment. The solid phasepeptide synthesis was performed manually, automatically on the Tributepeptide synthesizer (Protein Technologies Inc., Tucson, Ariz.) or by acombination of the manual and automatic methods.

Couplings of Fmoc-protected amino acids on the Tribute synthesizer weremediated with HBTU/NMM in DMF except for cysteine derivatives that werecoupled with DIC/HOBt in DMF. Single cycles of 30-60 min. with a 5-foldexcess of activated Fmoc-protected amino acids were used during thesynthesis. Removal of the Fmoc protecting group was monitored by UV.Multiple (up to 10 times, as needed) two-minute washes of the peptideresin with 20% piperidine in DMF were performed.

DIC/HOBt mediated couplings in DMF were employed for all amino acids inmanual mode. Single cycles of at least 2 h with a 3-fold excess ofactivated Fmoc-protected amino acids were used during the synthesis. Thecompleteness of couplings was assessed with the ninhydrin (Kaiser) test.Removal of the Fmoc protecting group was achieved with a single 30 min.wash of the peptide resin with 20% piperidine in DMF.

After the peptide fragment containing alpha carbons 1-9 was assembledthe position 8 side chain protecting group was removed. Peptide resinsprotected with the Mtt group were treated with the HIPF/TFE/TIS/DCM4/2/1/13 (v/v/v/v) cocktail (3 times for 1 h). To remove the ivDdeprotecting group the peptide resins were treated with 2% hydrazine/DMF(3 times for 10 min.). After the orthogonal protecting group was removedthe remaining part (residues 10-18) of the peptide was assembled byadding each amino acid sequentially.

Upon completion of the peptide synthesis, the peptide resins were washedwith DCM and dried in vacuo. The resins were treated with TFA/H₂O/TIS96:2:2 (v/v/v) for 2 h to remove the side-chain protecting groups withconcomitant cleavage of the peptide from the resin. The peptides werefiltered, precipitated with diethyl ether and decanted. The precipitatewas dissolved in 10 mL of neat TFA and the solution was subsequentlypoured into 200 mL of 10% acetonitrile in water. The linear peptide wasoxidized with 0.1 M I₂/MeOH. The oxidizer solution was added dropwiseuntil yellow color persisted. The excess of iodine was reduced withsolid ascorbic acid. The pH was then adjusted to about 4 withconcentrated ammonia. The solution obtained was loaded directly onto anHPLC prep column and eluted with a gradient of component B (see tablebelow).

Each crude peptide was purified with buffer system P. The fractions witha purity exceeding 93%, determined by reverse-phase analytical HPLC,were pooled and reloaded onto the column and eluted with buffer T toprovide trifluoroacetate salts. To obtain acetate salts the fractionsfrom runs with buffer P were reloaded onto the column and the column waswashed with 5 volumes of 0.1 M ammonium acetate. The final product waseluted with buffer A. The fractions were pooled and lyophilized.

TABLE 1 Buffer Compositions Buffer Component A Component B P 0.25MTriethylammonium 60% acetonitrile, 40% Phosphate (TEAP) (pH 5.2)Component A T 0.1% Trifluoroacetic acid (TFA) 60% acetonitrile, 0.1% TFAA 2% Acetic acid (AcOH) 60% acetonitrile, 2% AcOH

To prepare the alkyl-linked (alkyl as substituent “Q” in Formula (I)hybrids, residues 1-9 were assembled with an orthogonal protecting group(Mtt or ivDde) in position 8 as described above. The orthogonalprotecting group was then removed and the 2-nitrobenzenesulfonyl groupwas introduced with 2-nitrobenzenesulfonyl chloride/2,4,6-collidine inDCM. The resulting resin-bound sulfonamide was alkylated with anappropriate primary alcohol (e.g. 5-Fmoc-amino-1-pentanol) under theMitsunobu reaction conditions (10 equivalents of alcohol/TPP/DIAD in dryDME, overnight). The remaining residues 10-18 were subsequently addedone-by-one and the 2-nitrobenzenesulfonyl was removed with 5% potassiumthiophenolate in DMF (3 times for 30 min.). The cleavage, cyclizationand purifications were performed as described above.

The compounds prepared were typically found to be at least about 90%pure, e.g., at least about 95% pure, or at least about 97% pure, or atleast about 98.5% pure.

Illustrative syntheses of some of the compounds described herein areprovided below.

2. Synthesis of Compound No. 2

The 1-9 fragment was assembled manually starting from 15 g (10 mmol) ofRink Amide AM resin (EMD Biosciences, catalog number 855004, 0.68mmol/g). DIC/HOBt mediated couplings in DCM/DMF (1:1 v/v, for Gly, Orn,Pro, Cys, Ile, Phe and Cys) or in DMF (Asn, Gln) were employed. Singlecycles of at least 2 h with a 1.5-3-fold excess of activatedFmoc-protected amino acids were used during the synthesis. Thecompleteness of couplings was assessed with the ninhydrin test. Removalof the Fmoc protecting group was achieved with a single 30 min. wash ofthe peptide resin with 20% piperidine in DMF. The following amino acidderivatives were used to assemble residues 1-9 of the resin-boundpeptide: Fmoc-Gly-OH, Fmoc-Orn(Mtt)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH andBoc-Cys(Trt)-OH. After the residue 1-9 peptide fragment has beenassembled the resin was washed thoroughly with DCM and treated with theDCM/HFIP/TFE/TIS 13:4:2:1 (v/v/v/v) cocktail (2×2 h, 200 mL each). Theresin was then washed with DCM, MeOH, DMF and DCM. The resin waswet-split at this point and the synthesis was continued at a 1 mmolscale. (The remainder of the split portion was used to synthesize othercompounds, according to the description herein.)

The 2-nitrobenzenesulfonyl group was introduced with2-nitrobenzenesulfonyl chloride (1.11 g, 5 mmol) and 2,4,6-collidine (1mL, 7.5 mmol) in DCM. After 2 h the ninhydrin test was negative. Theresulting resin-bound sulfonamide was washed with dry DME and suspendedin 5 mL of dry DME. 2.63 g (10 mmol) 5-Fmoc-amino-1-pentanol and 2.63 g(10 mmol) were subsequently added to the suspension followed by asolution of 1.97 mL (10 mmol) of DIAD and the resin was shakenovernight. An aliquot of the resin was cleaved to test the completenessof the alkylation. No substrate peak was detected by HPLC analysis ofthe cleaved peptide. The resin was split again and the synthesis wascarried on at a 0.2 mmol scale. The resin was then placed in twoautomatic synthesis vessels each containing about 0.1 mmol resin-boundintermediate peptide. The synthesis was continued in parallel fashion onthe Tribute peptide synthesizer. Single couplings (with each amino acid10-18 added, one-at-a-time) were mediated with HBTU/NMM in DMF with a5-fold excess of Fmoc-protected amino acids were used. The Fmocprotecting group was removed with two consecutive 10 min. washes with20% piperidine in DMF. The following derivatives were used in theautomatic synthesis: Fmoc-Glu-NH₂, Fmoc-Arg(Pbf)-OH, Fmoc-Pro-OH,Fmoc-Ala-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Phe-OH,Fmoc-D-Tyr(Me)-OH and PhAc-OH.

After the entire peptide has been assembled, the two resins were pooledand the 2-nitrobenzenesulfonyl group was removed with 5% potassiumthiophenolate in DMF (2 washes of 30 min. each). Upon completion of thepeptide synthesis, the peptide resin was washed with DCM and dried invacuo. The peptide was cleaved from the resin with 20 mL of TFA/H₂O/TIS96:2:2 (v/v/v) for 2 h. The resin was filtered off and TFA wasevaporated. The crude product was precipitated with diethyl ether anddecanted. The precipitate was dissolved in 10 mL of neat TFA and thesolution was subsequently poured into 200 mL of 10% acetonitrile inwater. The linear peptide was oxidized with 0.1 M I₂/MeOH. The oxidizersolution was added dropwise until yellow color persisted. The excess ofiodine was reduced with solid ascorbic acid. The pH was then adjusted toabout 4 with concentrated ammonia. The obtained solution was loadeddirectly onto an HPLC prep column and purified with buffer system Peluted with a gradient of component B (see table below). The fractionswith a purity exceeding 93%, determined by reverse-phase analyticalHPLC, were pooled and reloaded onto the column and eluted with buffer Tto provide trifluoroacetate salt. The fractions were pooled andlyophilized. 46.2 mg (0.018 mmol, 9% assuming 85% peptide content) ofwhite peptide powder was obtained.

The product purity was determined by analytical HPLC as 99.0% and theobserved M+H as 2213.8 (calc. M+H was 2214.1).

3. Synthesis of Compound No. 42

The fragment comprising residues 5-9 (referring to Formula (I)) wasassembled manually starting from 0.68 g (1 mmol) of Rink Amide AM resin(EMD Biosciences, catalog number 855004, 0.68 mmol/g). DIC/HOBt mediatedcouplings in DMF were employed. Single cycles of at least 2 h with a3-4-fold excess of activated Fmoc-protected amino acids were used duringthe synthesis. The completeness of couplings was assessed with theninhydrin test. Removal of the Fmoc protecting group was achieved with asingle 30 min. wash of the peptide resin with 20% piperidine in DMF. Thefollowing amino acid derivatives were used to assemble the residuenumbers 5-9 resin-bound peptide: Fmoc-Gly-OH, Fmoc-Dab(ivDde)-OH,Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH and Fmoc-Asn(Trt)-OH. After the fragmentcomprising residues numbered 5-9 was assembled, the resin was wet-splitand the synthesis was continued at a 0.3 mmol scale on the Tributepeptide synthesizer with UV monitoring. (The remainder of this productwas used in the synthesis of other compounds as described herein.)

Single couplings mediated with HBTU/NMM in DMF with a 5-fold excess ofFmoc-protected amino acids were used. The Fmoc protecting group wasremoved with several consecutive 2 min. washes with 20% piperidine inDMF. The following amino acid derivatives were used to assemble thefragment comprising residues numbered 1-4 (see Formula (I)) as aresin-bound peptide: Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH andBoc-Cys(Trt)-OH. After the residue number 1-4 fragment was assembled theivDde group was removed with 2% hydrazine/DMF (20 mL, 3×10 min.) and thesynthesis was continued on Tribute to introduce the linker (Q) and theresidues 10-18 of the peptide sequence. The synthesizer settings wereidentical as those used in the assembly of the 1-4 fragment. Thefollowing derivatives were used in this part of automatic synthesis:Boc-Lys(Fmoc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Glu-NH₂, Fmoc-Arg(Pbf)-OH,Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH,Fmoc-Phe-OH, Fmoc-D-Tyr(Me)-OH and PhAc-OH. After the entire peptidesequence has been assembled the resin was washed thoroughly with DCM andtreated with the DCM/HFIP/TFE/TIS 13:4:2:1 (v/v/v/v) cocktail (3×1 h, 20mL each). The resin was then washed with DCM and DMF and acetylated withacetic anhydride (0.28 mL, 3 mmol) in DMF. Finally, the resin was washedwith DMF, MeOH and DCM and dried in vacuo. The peptide was cleaved fromthe resin with 20 mL of TFA/H₂O/TIS 96:2:2 (v/v/v) for 2 h. Thesubsequent steps were the same as in the synthesis of compound 2. Thefractions were pooled and lyophilized. 249.6 mg (0.088 mmol, 29%assuming 85% peptide content) of white peptide powder was obtained.

The product purity was determined by analytical HPLC as 95.3% and theobserved M+H was 2413.0 (calc. M+H=2413.2).

4. Synthesis of Compound No. 47

The fragment comprising residues numbered 5-9 (see Formula (I)) wasassembled manually starting from 0.6 g (1 mmol) of Rink Amide ChemMatrixresin (PCAS BioMatrix Inc, catalog number 7-600-1310, 0.6 mmol/g).DIC/HOBt mediated couplings in DMF were employed. Single cycles of atleast 2 h with a 3-4-fold excess of activated Fmoc-protected amino acidswere used during the synthesis. The completeness of couplings wasassessed with the ninhydrin test. Removal of the Fmoc protecting groupwas achieved with a single 30 min. wash of the peptide resin with 20%piperidine in DMF. The following amino acid derivatives were used toassemble the 1-9 resin-bound peptide: Fmoc-Gly-OH, Fmoc-Dab(ivDde)-OH,Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Hgn(Trt)-OH,Fmoc-Ile-OH, Fmoc-Phe-OH and Boc-Cys(Trt)-OH. After the 1-9 peptidefragment was assembled, the resin was washed 3 times with 20 mL of 2%hydrazine/DMF and wet-split at this point and the synthesis wascontinued at the 0.3 mmol scale on the Tribute peptide synthesizer withUV monitoring to introduce the linker (Q) and the residue 10-18 peptidesequence. (The remainder of the 1-9 residue resin product was used tosynthesis other compounds described herein)

Single couplings mediated with HBTU/NMM in DMF with a 5-fold excess ofFmoc-protected amino acids were used in the automatic synthesis. TheFmoc protecting group was removed with several consecutive 2 min. washeswith 20% piperidine in DMF. The following derivatives were used in theautomatic synthesis: Boc-Lys(Fmoc)-OH, Fmoc-Glu-NH₂, Fmoc-Arg(Pbf)-OH,Fmoc-Pro-OH, Fmoc-Cit-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH,Fmoc-Phe-OH, Fmoc-D-Tyr(Me)-OH and PhAc-OH. Upon completion of thepeptide synthesis, the peptide resin was washed with DCM and dried invacuo. The peptide was cleaved from the resin with 20 mL of TFA/H₂O/TIS96:2:2 (v/v/v) for 2 h. The subsequent steps were the same as in thesynthesis of compound 2. The fractions were pooled and lyophilized.174.3 mg (0.063 mmol, 21% assuming 85% peptide content) of white peptidepowder was obtained.

The product purity was determined by analytical HPLC as 96.9% and theobserved M+H was 2343.2 (calc. MH=2343.1).

5. Synthesis of Compound No. 29 by Boc/Fmoc strategy.

The fragment comprising residues 8-9 (referring to Formula (I)) wasassembled manually starting from 5.00 g (3.5 mmol) of MBHA resin (EMDBiosciences, catalog number 855006, 0.70 mmol/g). DCC or DIC/HOBtmediated couplings in DCM were employed. Single cycles of at least 2 hwith a 2-4-fold excess of activated Boc-protected amino acids were usedduring the synthesis. The completeness of couplings was assessed withthe ninhydrin test. Removal of the Boc protecting group was achievedwith two consecutive washes (5 and 25 min.) of the peptide resin with50% TFA/DCM containing 1% m-cresol. Neutralization of the peptide resinwas accomplished with two 5 min. washes with 5% TEA/DCM. The followingamino acid derivatives were used to assemble the residue numbers 8-9resin-bound peptide: Boc-Gly-OH and Boc-Dab(Fmoc)-OH. After the fragmentcomprising residues numbered 8-9 was assembled, the resin was split andthe synthesis was continued manually at a 0.5 mmol scale. (The remainderof this product was used in the synthesis of other compounds asdescribed herein.)

The fragment comprising residues numbered 2-7 (see Formula (I)) wassubsequently assembled using synthetic methods described for the 8-9fragment. The following derivatives were used in this segment:Boc-Pro-OH, Boc-Cys(Mob)-OH, Boc-Asn-OH, Boc-Gln-OH, Boc-Ile-OH andBoc-Phe-OH. The resin was split again and the synthesis was continuedmanually at a 0.13 mmol scale. The position 1 amino acid was introducedas Z(2-C1)-Cys(Mob)-OH and the Fmoc group was removed with twoconsecutive washes with 25% piperidine in DMF (5 and 20 min.,respectively). Fmoc-Lys(Boc)-OH was then coupled and the remainingfragment comprising residues numbered 10-18 (see Formula (I)) wassubsequently assembled by Boc chemistry. The following amino acidderivatives were used to synthesize this fragment: Boc-Glu-NH₂,Boc-Arg(Tos)-OH, Boc-Pro-OH, Boc-Ala-OH, Boc-Asn-OH, Boc-Gln-OH,Boc-Phe-OH, Boc-D-Tyr(Me)-OH and PhAc-OH. After the entire peptidesequence has been assembled the resin was washed thoroughly with DMF andtreated with 25% piperidine in DMF (5 and 20 min) The resin was thenwashed with DMF, suspended in NMP/DMSO (1:1, v/v) and guanylated with1H-Pyrazole-1-carboxamidine HCl (Aldrich #02729LB)/DIPEA. Finally, theresin was washed with DMF, MeOH and DCM and dried in vacuo. The peptidewas cleaved from the resin with 20 mL of HF/anisole 20:1 (v/v) for 1.5 hat 0° C. The resin/crude peptide was washed with 100 mL of ethyl etherand the peptide was extracted with 100 mL of acetic acid/water 3:1,(v/v). The subsequent steps were the same as in the synthesis ofcompound 2. The fractions were pooled and lyophilized. 47.5 mg (0.018mmol, 7% assuming 85% peptide content) of white peptide powder wasobtained.

The product purity was determined by analytical HPLC as 100.0% and theobserved M+H was 2285.1 (calc. M+H=2285.2).

6. Analytical Data for Example Compounds

Additional example compounds were prepared, in general using syntheticmethods analogous to those described above. Analytical data for examplecompounds that were prepared are provided in Table 2.

TABLE 2 Analytical Data for Example Compounds Mass Spectrometric Data(M + H) Com- Calcu- Ob- pound Structure lated served 1

2412.0 2412.0 2

2214.1 2213.8 3

2398.2 2398.3 4

2228.1 2227.8 5

2327.2 2326.8 6

2327.2 2327.2 7

2299.1 2299.2 8

2242.1 2242.0 9

2284.2 2284.0 10

2285.1 2284.9 11

2230.1 2230.2 12

2271.1 2271.2 13

2280.1 2280.2 14

2271.1 2271.2 15

2300.1 2300.2 16

2243.1 2243.2 17

2222.5 2222.4 18

2243.1 2243.2 19

2220.1 2220.2 20

2285.1 2285.4 21

2194.1 2194.2 22

2315.2 2314.8 23

2215.1 2215.0 24

2362.2 2362.2 25

2346.1 2346.0 26

2384.2 2384.2 27

2346.1 2346.0 28

2257.1 2257.0 29

2285.1 2285.2 30

2244.1 2244.2 31

2329.1 2329.4 32

2301.1 2031.2 33

2267.1 2267.2 35

2300.1 2300.2 36

2294.1 2294.4 37

2342.1 2342.4 38

2243.1 2243.2 39

2243.1 2242.8 41

2371.2 2371.4 42

2413.2 2413.0 43

2483.3 2483.6 44

2329.1 2329.4 45

2334.1 2334.4 46

2280.1 2280.4 47

2343.1 2343.2 48

2344.1 2344.4 49

2329.1 2329.0 50

2257.1 2257.4 51

2257.1 2257.4 52

2343.1 2343.4 53

2257.1 2257.4 54

2243.1 2243.4 55

2329.1 2329.4 56

2243.1 2243.4 57

2329.1 2329.4 58

2427.2 2427.3 59

2258.1 2258.3 60

2229.1 2229.2 61

2314.1 2314.4 62

2257.1 2257.3 63

2229.1 2229.2 64

2257.1 2257.3 65

2257.1 2257.3 66

2229.1 2229.3

7. Biological Data for Illustrative Compounds a. Agonist Activity atVasopressin V1a receptors

The method is designed to determine the agonist activity of compounds atthe vasopressin V1a receptors in a cell-based Fluorescence Imaging PlateReader (FLIPR) assay and to evaluate their EC₅₀ values (theconcentration of a compound that produces 50% of the maximum possibleresponse). Efficacy (% MPE) is also determined as the percentage ofmaximal possible effect. This agonist assay utilizes cells from a stablecell line (HEK-flpin) expressing the vasopressin V1a receptor.Intracellular calcium increase in response to agonist is measuredthrough real-time fluorescence of an intracellular calcium-sensitivedye. Cells are exposed to varying concentrations of test agonistcompounds whereupon release of intracellular calcium is measured todetermine the agonist potency and efficacy.

Materials

Human cells used were from the Flp-In™ 293 cell line (HEK-flpin). Thecell line stably expresses the lacZ-Zeocin™ fusion gene and is designedfor use with the Flp-In™ expression vector containing the gene ofinterest and the Flp recombinase expression plasmid, pOG44. The cellline contains a single integrated Flp Recombination Target (FRT) sitefrom pFRT/lacZeo or pFRT/lacZeo2. To generate the HEK-flpin cell linestably expressing the human V1aR, the cells were co-transfected with theFlp-In™ expression vector containing the gene of interest(pcDNA5/FRT-hV1aR) and the Flp recombinase expression plasmid pOG44. Flprecombinase mediates insertion of the Flp-In™ expression vector into thegenome at the integrated FRT site through site-specific DNArecombination. Stable cell lines expressing the hV1aR from the Flp-In™expression vector can be generated by selection using hygromycin B. SeeLife Technologies/Invitrogen manual, Growth and Maintenance of Flp-In™Cell Lines, Version E, published Feb. 12, 2003, for detailedinformation.

Arginine vasopressin (AVP) was used as reference agonist in the assay.Efficacy of this compound was set to be 100%. A stock solution of 5 mMwas made up in DMSO and stored at −20° C.

Reagents used were the following: Dimethyl sulfoxide (DMSO) (Sigma,D8779); Dulbecco's Modification of Eagle's Medium (DMEM) with glucoseand sodium pyruvate without L-glutamine (Mediatech, 15-013-CV); FetalBovine Serum-Heat inactivated (FBS-HI) (Invitrogen, 16140-071); FLIPRCalcium 4 Assay Kit, bulk format (Molecular Devices, R8141); Hanks'Balanced Salt Solution (HBSS) (Invitrogen, 14025-092); Hepes Buffer, pH7.2 (Mediatech, 25-060-CI); Hygromycin B 50 mg/mL (Mediatech,30-240-CR); GlutaMAX™-I Supplement, 200 mM (Invitrogen, 35050-061);Phenol red-free DMEM: DMEM with 4.5 g/L glucose and sodium pyruvatewithout L-glutamine and phenol red (Mediatech, 17-205-CV); Probenecid(Sigma-Aldrich, P-8761); and Trypsin EDTA: 0.05% Trypsin/0.53 mM EDTA(Mediatech, 25-052-CI).

Supplies used were the following: 384 well black clear bottom,poly-D-lysine-coated Assay Plate (Corning, 3712); 384 well V-bottomplate, Dilution Plate (Greiner, 781280); Polystyrene test tube (BDBiosciences, 352057); and T175 Cell⁺ Flask (Sarstedt, 83.1812.302).Equipment and software used were the following: Fluorometric ImagingPlate Reader (FLIPR Tetra) (Molecular Devices); and ActivityBasesoftware (IDBS, UK).

HEK-flpin-hV1aR, cmcqV1aR, dV1aR and pV1aR cells were maintained in DMEMcontaining 10% (v/v) FBS-HI, 4 mM GlutaMAX™-I, 25 μg/mL Hygromycin B at37° C. under 5% CO₂ in a humidified atmosphere. Subculture was achievedby splitting semi-confluent cultures 1:3 to 1:6. On the day prior to theassay, cells were removed from culture flasks using Trypsin EDTA andharvested in phenol-red free DMEM containing 10% FBS-HI, 4 mMGlutaMAX™-I. Cells were seeded into 384-well, black clear bottom,poly-D-lysine-treated plates (20 μl/well), at cell density of 20,000cells/well and incubated overnight.

All compounds were made up in 100% DMSO at 10 mM stock concentrationsand stored at −20° C. The compounds were allowed to thaw just before theassay. Compounds were assayed in duplicate at descending concentrationsin half-log increments with the highest concentration of 1 or 10 μmdepending on the potency of the compounds. Typical dilution procedure of10× final assay concentration involved a 1:100 top dilution (e.g., 2 μlStock into 198 μl dilution medium) followed by half-log serial dilutions(e.g., 25.3 μA into 54.7 μl dilution medium supplemented with 1% DMSO(v/v)). (Dilution media consisted of phenol-red free DMEM containing 10%FBS-HI, 4 mM GlutaMAX™-I). The reference (AVP) was tested at 1 μmhighest concentration (e.g. 1 μl stock into 999 μl dilution medium). Thefinal DMSO concentration in the assay was 0.1%. The reference (AVP) andthe Blank consisting of dilution media supplemented with 0.1% DMSO (v/v)were included in each study.

EC₅₀ determination

Loading Buffer was prepared by dissolving 1 vial of Calcium 4 Assayreagent in 100 mL of 1×HBSS-20 mM Hepes buffer. Probenecid wasresuspended at 250 mM in 1 M NaOH followed by a 1:100 dilution in theLoading Buffer for a final working concentration of 2.5 mM. The pH wasadjusted to 7.4.

The cells were loaded with Loading Buffer as follows. Cell plates wereremoved from the incubator and 20 μl of Loading Buffer containingprobenecid (2.5 mM) was added to each well. The cells were incubated for1 hr at 37° C. under 5% CO₂ in a humidified atmosphere. The calciumimage was obtained as follows. FLIPR Tetra was setup with the followingdefault parameters and a read mode with an excitation wavelength of470-495 nm and an emission wavelength of 515-575 nm as determined byfilter selection: Gain of 20; Excitation Intensity of 80% (Default);Exposure Time of 0.4 seconds (Default).

The cell plates were transferred to FLIPR Tetra, along with a 384 wellV-bottom plate pre-loaded with half-log concentrations of test compoundsat 10× final test concentrations. The remaining steps of the assay werecarried forward by FLIPR Tetra. A baseline reading was taken at 1-second(s) intervals for 5s followed by the addition of 5 μl of 10× compounds(test, reference, or Blank). The agonist-induced fluorescence signal wasthen measured for 180 s with initial 120 readings at 1-second intervalsfollowed by 20 readings at 3-second intervals. Overall, each well in theFLIPR assay was composed of the following components in a total volumeof 50 μl: 20 μl cells; 20 μl Calcium 4 Loading Buffer; 4.4 μl 10× testor reference compound.

Averaged EC₅₀ (in nM) and Efficacy Average (as compared to AVP) arepresented in Table 3.

TABLE 3 Assay Results Compound # EC₅₀ (Avg) nM Efficacy Avg. (%) AVP0.07 100.0 1 1.0 30 2 0.69 52 3 2.9 39 4 1.5 24 5 1.3 28 6 2.5 287 >10,000 24 8 >10,000 50 9 >10,000 34 10 >10,000 26 11 2.2 51 12 2.3 3913 2.4 48 14 2.1 37 15 2.3 44 16 2.4 46 17 2.9 62 18 3.9 49 19 2.5 50 202.7 42 21 1.5 47 22 0.95 29 23 1.7 51 24 2.3 33 25 1.4 49 26 0.93 32 271.0 70 28 1.2 44 29 1.2 39 30 1.1 50 31 0.83 63 32 1.0 56 33 1.1 50 351.2 43 36 1.2 46 37 1.3 44 38 1.4 46 39 1.8 48 41 1.2 37 42 1.0 37 431.4 59 44 2.0 40 45 0.80 72 46 1.4 62 47 1.8 45 48 1.4 67 49 0.76 55 500.90 40 51 1.4 43 52 1.5 47 53 1.7 43 54 1.4 51 55 1.7 56 56 1.8 60 571.4 63 58 2.6 26 59 1.7 26 60 2.3 42 61 2.5 38 62 2.5 31 63 1.1 36 642.9 42 65 4.5 31 66 2.3 30

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages and modifications are within the scope of thefollowing claims.

1. A compound according to formula (I):

or a salt thereof, wherein: R¹ is selected from (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylNH, Ar¹-L¹- and unsubstituted orsubstituted cycloalkyl; Ar¹-L¹- is selected from Ar¹—, Ar¹—CH₂—,Ar¹—CH₂CH₂—, Ar¹—O—, Ar¹—CH₂O—, Ar¹NH— and Ar¹—CH₂NH—; Ar¹ isunsubstituted aryl or substituted aryl; R² is selected from hydrogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy and halogen; R³ is selected from(C₁-C₆)alkyl, unsubstituted or substituted cycloalkyl and Cy³-CH₂—; Cy³-is unsubstituted or substituted aryl or unsubstituted or substitutedcycloalkyl; R⁴ is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)halo alkyl, —((C₁-C₆)alkylene)-OR^(4a),—((C₁-C₆)alkylene)-NR^(4a) ₂, —((C₁-C₆)alkylene)-S(C₁-C₆)alkyl,—(C₁-C₆)alkylene)C(═O)OR^(4a) ₂, —((C₁-C₆)alkylene) C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-C(═NR^(4a))NR^(4a) ₂, —((C₁-C₆)alkylene)OC(═O)R^(4a), —((C₁-C₆)alkylene)-OC(═O)OR^(4a), —((C₁-C₆)alkylene)OC(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)NR^(4a)C(═O)R^(4a),—((C₁-C₆)alkylene) NR^(4a)C(═O)OR^(4a),—((C₁-C₆)alkylene)NR^(4a)C(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)—NR^(4a)C(═NR^(4a))NR^(4a) ₂, Ar⁴ and —((C₁-C₆)alkylene)-Ar⁴; eachR^(4a) is independently selected from hydrogen and C₁-C₆)alkyl; Ar⁴ isselected from unsubstituted or substituted aryl and unsubstituted orsubstituted heteroaryl; R⁵ is selected from —(C₁-C₆)alkylene)-NR^(5a) ₂and —(C₁-C₆)alkylene)-NR^(5a)C(═NR⁵a)NR^(5a) ₂; each R^(5a) isindependently selected from hydrogen and C₁-C₆)alkyl; Q is selected fromthe groups Q¹, Q², Q³ and Q⁴:

a and b denote the bonds attaching Q to the remainder of the molecule;R⁶ is selected from hydrogen, (C₁-C₆)alkyl and —C(═NR⁶a)NR⁶a₂; eachR^(6a) is hydrogen or C₁-C₆)alkyl; R⁷ is selected from (C₁-C₆)alkyl,unsubstituted aryl, substituted aryl, unsubstituted cycloalkyl andsubstituted cycloalkyl; R⁸ is selected from NH₂ and hydroxyl; R⁹ isselected from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)halo alkyl, —((C₁-C₆)alkylene)-OR^(9a), —((C₁-C₆)alkylene)-NR⁹a₂,—((C₁-C₆)alkylene)-SR^(9a), —((C₁-C₆)alkylene)-C(═O)OR⁹a₂,—((C₁-C₆)alkylene) C(═O)NR⁹a₂, —((C₁-C₆)alkylene)-C(═NR⁹a)NR⁹a₂,—((C₁-C₆)alkylene) OC(═O)R^(9a), —((C₁-C₆)alkylene)-OC(═O)OR^(9a),—((C₁-C₆)alkylene) OC(═O)NR⁹a₂, —((C₁-C₆)alkylene)NR^(9a)C(═O)R^(9b),—((C₁—C6)alkylene) NR^(9a)C(═O)OR^(9a),—((C₁-C₆)alkylene)NR^(9a)C(═O)NR^(9a) ₂, —((C₁-C₆)alkylene)—NR^(9a)C(═NR⁹a)NR⁹a₂, Ar⁹ and —((C₁-C₆)alkylene)-Ar⁹; each R⁹a isindependently selected from hydrogen and C₁-C₆)alkyl; each R^(9b) isindependently selected from hydrogen and (C₁-C₁₀)alkyl; Ar⁹ is selectedfrom unsubstituted aryl, substituted aryl, unsubstituted heteroarylsubstituted heteroaryl; R¹⁰ is selected from —(C₁-C₆)alkylene)-OR^(10a),—((C₁-C₆)alkylene)-C(═O)NR^(10a) ₂ and Ar¹⁰—CH₂—; Ar¹⁰ is unsubstitutedheteroaryl or substituted heteroaryl; each R^(10a) is selected fromhydrogen and (C₁-C₆)alkyl; Ar is selected from aryl or substituted aryl;each X is NH and each Y is C═O; or each X is C═O and each Y is NH; m is0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3 or 4; o is 1 or 2; p is 1, 2 or 3;and r is 0, 1, 2, 3, 4, 5 or 6; provided that R⁹ is hydrogen if r isgreater than one.
 2. A compound or salt thereof according to claim 1,wherein: R¹ is selected from (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₁-C₁₀)alkylNH, Ar¹-L¹- and Cy¹; Cy¹ is unsubstituted cycloalkyl orcycloalkyl substituted by 1, 2 or 3 substituents independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen,C₁-C₆)haloalkyl, —OR¹a and oxo; Ar¹ is unsubstituted aryl or arylsubstituted by 1, 2 or 3 substituents independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl,—CN, —NO₂, —OR^(1a), —NR^(1a) ₂ and —NR^(1a)C(═O)R^(1a); each R^(1a) isindependently selected from hydrogen and (C₁-C₆)alkyl; Cy³ is Ar³ orunsubstituted cycloalkyl or cycloalkyl substituted by 1, 2 or 3substituents independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, C₁-C₆)haloalkyl, —OR^(3a) and oxo; Ar³— isunsubstituted aryl or aryl substituted by 1, 2 or 3 substituentsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(3a), —NR^(3a)₂ and —NR^(3a)C(═O)R^(3a); each R^(3a) is independently selected fromhydrogen and (C₁-C₆)alkyl; Ar⁴ is selected from unsubstituted aryl,unsubstituted heteroaryl and aryl and heteroaryl substituted by 1, 2 or3 substituents independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(4b), —NR^(4b)₂ and —NR^(4b)C(═O)R^(4b); each R^(4b) is selected from hydrogen and(C₁-C₆)alkyl; R⁷ is selected from (C₁-C₆)alkyl, Ar⁷ and Cy⁷; Cy⁷ isunsubstituted cycloalkyl or cycloalkyl substituted by 1, 2 or 3substituents independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, C₁-C₆)haloalkyl, —OR^(7a) and oxo; Ar⁷ isunsubstituted aryl or aryl substituted by 1, 2 or 3 substituentsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(7a), —NR^(7a)₂ and —NR^(7a)C(═O)R^(7a); each R^(7a) is independently selected fromhydrogen and (C₁-C₆)alkyl; Ar⁹ is selected from unsubstituted aryl,unsubstituted heteroaryl and aryl and heteroaryl substituted by 1, 2 or3 substituents selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl, —CN, —NO₂, —OR^(9c), —NR^(9c)₂ and —NR^(9c)C(═O)R^(9c); each R^(9c) is selected from hydrogen and(C₁-C₆)alkyl; Ar¹⁰ is selected from unsubstituted heteroaryl andheteroaryl substituted by 1, 2 or 3 substituents selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halogen, (C₁-C₆)haloalkyl,—CN, —NO₂, —OR^(10b), —NR^(10b) ₂ and —NR^(10b) _(c)(═O)R^(10b); eachR^(10b) is independently selected from hydrogen and (C₁-C₆)alkyl; Ar isselected from unsubstituted aryl and aryl substituted by 1, 2 or 3substituents selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,halogen, (C₁-C₆)haloalkyl, —CN, NO₂, —OR^(Ar), —NR^(Ar) ₂ and—NR^(Ar)C(═O)R^(Ar); and each R^(Ar) is independently selected fromhydrogen and (C₁-C₆)alkyl.
 3. A compound or salt thereof according toclaim 1, wherein R¹ is (C₁-C₁₀)alkyl, (C₅-C₇)cycloalkyl or Ar¹—CH₂—. 4.A compound or salt thereof according to claim 3, wherein R¹ is isobutyl,n-hexyl, cyclohexyl or benzyl.
 5. (canceled)
 6. A compound or saltthereof according to claim 1, wherein R² is selected from hydroxy,(C₁-C₆)alkoxy and halogen.
 7. A compound or salt thereof according toclaim 6, wherein R² is (C₁-C₆)alkoxy.
 8. A compound or salt thereofaccording to claim 6, wherein R² is methoxy.
 9. A compound or saltthereof according to claim 1, wherein R³ is selected from (C₁-C₆)alkyland Ar^(a)CH₂—, wherein Ar³— is unsubstituted or halo-substituted aryl;10-11. (canceled)
 12. A compound or salt thereof according to claim 1,wherein R³ is selected from (C₁-C₆)alkyl and Ar³—CH₂—, wherein Ar^(a) isphenyl or halo-substituted phenyl.
 13. A compound or salt thereofaccording to claim 12, wherein R³ is selected from s-butyl, neopentyl,benzyl and 4-chlorobenzyl.
 14. A compound or salt thereof according toclaim 1, wherein R⁴ is selected from (C₁-C₆)alkyl,—((C₁-C₆)alkylene)-OR^(4a), —((C₁-C₆)alkylene)-NR^(4a) ₂,—((C₁-C₆)alkylene) C(═O)NR^(4a) ₂,—((C₁-C₆)alkylene)-NR^(4a)C(═O)NR^(4a) ₂, —((C₁-C₆)alkylene)—NR^(4a)C(═NR^(4a))NR^(4a) ₂ and —((C₁-C₆)alkylene)-Ar⁴.
 15. A compoundor salt thereof according to claim 14, wherein R⁴ is selected from(C₁-C₆)alkyl, —(CH₂)₁₋₆—OR^(4a), —(CH₂)₁₋₆—NR^(4a) ₂,—(CH₂)₁₋₆—C(═O)NR^(4a) ₂, —(CH₂)₁₋₆—NR^(4a)C(═O)NR^(4a) ₂,—(CH₂)₁₋₆—NR^(4a)C(═NR^(4a))NR^(4a) ₂ and —(CH₂)₁₋₆—Ar⁴. 16-17.(canceled)
 18. A compound or salt thereof according to claim 15, whereineach R^(4a) is hydrogen or methyl and Ar⁴ is imidazolyl or indolyl.19-20. (canceled)
 21. A compound or salt thereof according to claim 14,wherein R⁴ is selected from Me, isobutyl, —CH₂OH, —(CH₂)₂—NH₂,—(CH₂)₃—NH₂, —(CH₂)₄—NH₂, —(CH₂)₂—C(═O)NH₂, —(CH₂)₃—NHC(═NH)NH₂,—(CH₂)₃—NHC(═O)NH₂ and —CH₂(1H-imidazol-4-yl).
 22. A compound or saltthereof according to claim 1, wherein R⁵ is selected from—(CH₂)₁₋₆—NR^(5a) ₂ and —(CH₂)₁₋₆—NR^(5a)C(═NR^(5a))NR^(5a) ₂.
 23. Acompound or salt thereof according to claim 22, wherein each R^(5a) isindependently selected from hydrogen and methyl.
 24. (canceled)
 25. Acompound or salt thereof according to claim 22, wherein R⁵ is—(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —(CH₂)₄—NH₂ or —(CH₂)₃—NHC(═NH)NH₂. 26.(canceled)
 27. A compound or salt thereof according to claim 1, whereinR⁷ is (C₁-C₆)alkyl or (C₄-C₇)cycloalkyl.
 28. (canceled)
 29. A compoundor salt thereof according to claim 27, wherein R⁷ is s-butyl.
 30. Acompound or salt thereof according to claim 1, wherein R⁸ is —NH₂.
 31. Acompound or salt thereof according to claim 1, wherein R⁸ is —OH.
 32. Acompound or salt thereof according to claim 1, wherein R¹⁰ is selectedfrom —(CH₂)₁₋₆—C(═O)NR^(10a) ₂ and Ar¹⁰—CH₂—.
 33. (canceled)
 34. Acompound or salt thereof according to claim 1, wherein each R^(10a) ishydrogen or methyl and Ar¹⁰ is pyridyl. 35-36. (canceled)
 37. A compoundor salt thereof according to claim 1, wherein R¹⁰ is selected from1-hydroxyethyl, —(CH₂)₂—C(═O)NH₂ and 3-pyridyl-CH₂—.
 38. (canceled) 39.A compound or salt thereof according to claim 1, wherein Ar is phenyl orsubstituted phenyl.
 40. A compound or salt thereof according to claim39, wherein Ar is phenyl.
 41. A compound or salt thereof according toclaim 1, wherein each X is NH and each Y is C═O.
 42. A compound or saltthereof according to claim 1, wherein each X is C═O and each Y is NH.43. A compound or salt thereof according to claim 1, wherein m is 0, 1,2, 3 or
 4. 44-45. (canceled)
 46. A compound or salt thereof according toclaim 1, wherein o is 1 or
 2. 47. (canceled)
 48. A compound or saltthereof according to claim 1, wherein p is 1, 2 or
 3. 49-50. (canceled)51. A compound or salt thereof according to claim 1, wherein Q is Q¹.52. A compound or salt thereof according to claim 51, wherein n is 1, 2or
 3. 53-54. (canceled)
 55. A compound or salt thereof according toclaim 51, wherein Q¹ is ^(a)-NH(CH₂)₄CH(NH₂)—C(═O)—^(b),^(a)-NH(CH₂)₄CH(NHC(═NH)NH₂)—C(═O)—^(b) or^(a)-C(═O)(CH₂)₂CH(NH₂)—C(═O)—^(b).
 56. A compound or salt thereofaccording to claim 51, wherein Q¹ is^(a)-NH(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NH(CH₂)₄C^((S))H(NHC(═NH)NH₂)—C(═O)—^(b) or^(a)-C(═O)(CH₂)₂C^((S))H(NH₂)—C(═O)—^(b) or^(a)-C(═O)(CH₂)₂C^((R))H(NH₂)—C(═O)—^(b).
 57. A compound or salt thereofaccording to claim 1, wherein Q is Q³.
 58. A compound or salt thereofaccording to claim 57, wherein n is
 3. 59. A compound or salt thereofaccording to claim 57, wherein r is 0 or
 3. 60-61. (canceled)
 62. Acompound or salt thereof according to claim 61, wherein R⁹ is selectedfrom —(CH₂)₁₋₆—NR^(9a) ₂ and —(CH₂)₁₋₆—NR^(9a)C(═O)R^(9b), each R^(9a)is hydrogen and each R^(9b) is hydrogen or (C₁-C₆)alkyl. 63-69.(canceled)
 70. A compound or salt thereof according to claim 1, whereinQ is Q¹ or Q³ and R⁶ is hydrogen or —C(═NH)NH₂.
 71. A compound accordingto claim 57, wherein Q³ is^(a)-NH(CH₂)₄—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b),^(a)-NHCH((CH₂)₄NH₂)—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b),^(a)-NHCH((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b) or^(a)-NHCH((CH₂)₄NHHeptanoyl)-C(═O)—NH—(CH₂)₄CH(NH₂)—C(═O)—^(b).
 72. Acompound according to claim 57, wherein Q³ is^(a)-NH(CH₂)₄—C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NHC^((S))H((CH₂)₄NH₂)—C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NHC^((S))H((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b),^(a)-NHC^((S))H((CH₂)₄NHAc)—C(═O)—NH—(CH₂)₄C^((R))H(NH₂)—C(═O)—^(b) or^(a)-NHC^((S))H((CH₂)₄NHHeptanoyl)-C(═O)—NH—(CH₂)₄C^((S))H(NH₂)—C(═O)—^(b).73. A compound or salt thereof according to claim 1, wherein Q is Q².74. A compound according to claim 73, wherein n is 0, 1, 2 or
 3. 75-77.(canceled)
 78. A compound according to claim 74, wherein Q² is^(a)-NH(CH₂)₄-^(b), ^(a)-NH(CH₂)₅-^(b), ^(a)-NH(CH₂)₆-^(b),^(a)-C(═O)—(CH₂)₃-^(b) or a-C(═O)—(CH₂)₅-^(b).
 79. A compound or saltthereof according to claim 1, wherein Q is Q⁴.
 80. A compound accordingto claim 79, wherein n is 1, 2 or
 3. 81-82. (canceled)
 83. A compoundaccording to claim 79, wherein r is 1, 2 or
 3. 86. A compound accordingto claim 79, wherein Q⁴ is ^(a)-NH—(CH₂)₂—C(═O)—NH—(CH₂)₅-^(b),^(a)-NH—(CH₂)₄—C(═O)—NH—(CH₂)₆-^(b),^(a)-C(═O)—(CH₂)₂—C(═O)—NH—(CH₂)₆-^(b) or^(a)-C(═O)—(CH₂)₃—C(═O)—NH—(CH₂)₄-^(b).
 87. A compound selected fromcompounds of the following formulae, and salts thereof:


88. A pharmaceutical composition comprising a compound according toclaim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 89. A method of treating acomplication arising from cirrhosis, comprising administering to anindividual in need of such treatment an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 90.A method according to claim 89, wherein the complication arising fromcirrhosis is a complication wherein increasing blood pressure istherapeutically beneficial.
 91. A method according to claim 89, whereinthe complication is spontaneous bacterial peritonitis, type IIheptoarenal syndrome (HRS2) or refractory ascites.
 92. A method oftreatment for increasing blood pressure, comprising administering to anindividual in need of such treatment an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 93.A method of treatment for a condition selected from hypovolemic shock;vasodilatory shock; bleeding esophageal varices; hepatorenal syndrome;type I hepatorenal syndrome; type II hepatorenal syndrome;anesthesia-induced hypotension; paracentesis-induced circulatorydysfunction; intra-operative blood loss; acute hemorrhage; blood lossassociated with burn debridement; blood loss associated with epistaxis;spontaneous bacterial peritonitis; refractory ascites; hypertensivegastropathy bleeding; sepsis; severe sepsis; septic shock; hypotension;cardiac arrest; trauma-related blood loss; vasodilatory shock induced bycardio-pulmonary bypass; milrinone-induced vasodilatory shock incongestive heart failure; anaphylactic shock; cardiovascular instabilityinduced by brain death; acute respiratory distress syndrome; acute lunginjury; shock induced by metformin intoxication; shock induced bymitochondrial disease; shock induced by cyanide poisoning; shock inducedby vascular leak syndrome induced by interleukin-2, another cytokine,denileukin diftitox or another immunotoxin, or by ovarianhyperstimulation syndrome; hypotension induced by end-stage renaldisease; inflammatory bowel disease; reperfusion injury; infantrespiratory distress syndrome; severe acute respiratory syndrome;ascites; vasodepressor syncope; vasovagal syncope; toxic shock syndrome;and idiopathic systemic capillary leak syndrome; or treatment forfacilitating cardiopulmonary resuscitation, the method comprisingadministering to an individual in need of such treatment an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.